Medicinal Mushrooms (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Introduction

Medicinal mushrooms have been used for hundreds of years, mainly in Asian countries, for treatment of infections. More recently, they have also been used in the treatment of pulmonary diseases and cancer. Medicinal mushrooms have been approved adjuncts to standard cancer treatments in Japan and China for more than 30 years and have an extensive clinical history of safe use as single agents or combined with chemotherapy.

More than 100 species of medicinal mushrooms are used in Asia. Some of the more commonly used species include Ganoderma lucidum (reishi), Trametes versicolor or Coriolus versicolor (turkey tail), Lentinus edodes (shiitake), and Grifola frondosa (maitake).

Studies have examined the effects of mushrooms on immune response pathways and on direct antitumor mechanisms. The immune effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, natural killer cells, and dendritic cells. The activity is generally considered to be caused by the presence of high-molecular-weight polysaccharides in the mushrooms, although other constituents may also be involved.

This cancer information summary provides an overview of the use of medicinal mushrooms in the treatment of cancer. This summary includes the history of research, reviews of laboratory and animal studies, and results of clinical trials on T. versicolor or C. versicolor (turkey tail). Sections describing results of clinical trials on other mushrooms will be added over time.

Turkey Tail and Polysaccharide-K

General Information

Turkey tail is a woody bracket polypore fungus that grows on dead logs worldwide. The scientific name of turkey tail is Trametes versicolor (L.) Lloyd, although it has been known by other names, notably Coriolus versicolor (L. ex Fr.) Quel. It is known as Yun Zhi in traditional Chinese medicine and Kawaratake (roof tile fungus) in Japan. The name turkey tail refers to its concentric rings of brown and tan, which resemble the tail feathers of a turkey. There are many other species of Trametes, some of which are difficult to distinguish from turkey tail. Internal transcribed spacer sequences alone have been found inadequate to distinguish turkey tail from other species of Trametes, so other molecular characters are required for that task.[1]

History

The fungus has been used in traditional Chinese medicine for many years to treat pulmonary diseases.[2,3] A purified hot water extract prepared from the cultivated fungal mycelium has been used in Japan for its immunomodulatory effects as an adjuvant treatment for cancer.[4,5,6]Polysaccharide -K (PSK) or krestin, from the mushroom T. versicolor, is an approved mushroom product used for cancer treatment in Japan. PSK is a proprietary formulation from the Kureha Corporation. PSK has been used as an adjunctive cancer treatment in thousands of patients since the mid-1970s. The safety record for PSK is well established in Japan. Few adverse events have been reported in patients treated with PSK. Polysaccharopeptide (PSP) is another extract from T. versicolor produced in China.

Laboratory/Animal/Preclinical Studies

Chemistry

The best known constituent of turkey tail is the glycoprotein mixture known as PSK. PSK is not a homogeneous substance, with a range of molecular weights averaging 9.4 kDa (range 5-300 kDa). The glycoprotein molecules are composed of a main chain beta-(1,4) glucan with beta-(1,3)- and beta-(1,6)-linked side chains. Small amounts of galactose, mannose, and arabinose have also been detected in the hydrolysate. Between 25% and 38% of the mass comes from a covalently linked protein whose amino acid composition has been reported.[4]

PSK radiolabeled with carbon-14 has been used to study the oral bioavailability and distribution of PSK in mice, rats, and rabbits. A fraction of the dose appears to be orally absorbed, more or less intact, and is excreted in bile over several hours. However, most of the radiolabeled dose is found in expired air, suggesting that the digestion of PSK may occur in the gut or the metabolism of absorbed PSK may occur somewhere else in the body.[7] A monoclonal antibody (specific for PSK) that neutralizes PSK's antitumor effects has been developed. It also validated the presence of PSK in implanted tumors.[8]

PSP, a very similar substance, has also been purified from a different strain of turkey tail; PSP and PSK differ somewhat in sugar composition.[2]

A lipid component of PSK has been separated by lipase treatment and found to have toll-like receptor 2 agonist activity, synergistic with the protein-bound beta-glucan. The lipid component was primarily linoleic acid, with smaller amounts of other fatty acids.[9]

The mitogen-activated protein kinase inhibitor hypothemycin [10] and the adipocyte fat accumulation-inhibitory cyclic peptide ternatin [11] have also been isolated from cultures of T. versicolor.

Mechanistic studies

Since the earliest reports of clinical benefits, other investigators have sought to define the mechanism of PSK's beneficial action. One group hypothesized that T-cell dysfunction, including apoptosis of peripheral blood T cells, commonly occurs in patients receiving chemotherapy.[12] They postulated that reversal of T-cell dysfunction induced by chemotherapy could reduce the adverse effects or enhance the antitumor effect. PSK is reported to enhance natural killer (NK) cell and T-cell activities by upregulation of interleukin-2 or interferon-gamma. Twenty patients with curatively resected stage III gastric cancer were randomly assigned to receive adjuvant therapy with the second-generation dihydropyrimidine dehydrogenase-inhibitory oral fluoropyrimidine S-1 alone (n = 10) or S-1 plus PSK (n = 10). At 5 weeks after adjuvant therapy, T-cell apoptosis was significantly higher in the S-1-alone group than in the S-1-plus-PSK group, leading the authors to conclude that PSK could partially prevent the T-cell apoptosis induced by S-1.

Another group of investigators studied the effect of PSK added to tegafur/uracil (UFT) chemotherapy compared with that of UFT alone.[13]Baseline immune parameters were comparable in the two groups. However, CD57-positive T cells decreased more significantly after surgery for patients treated with PSK than for those in the control group (P = .0486). These investigators had previously noted that a high CD57-positive cell count was an indicator of poor prognosis in patients with advanced gastric cancer, leading them to suggest that PSK may improve overall survival (OS) partly by inhibiting CD57-positive T cells.

Noting that hosts become immunocompromised at the time of tumor progression and that decreased expression of major histocompatibility complex (MHC) class I by the tumor is one mechanism that allows it to evade destruction by cytotoxic T lymphocytes, investigators conducted a retrospective study to evaluate the expression of MHC class I by immunohistochemical staining in the primary lesions of patients with stage II or stage III gastric cancer.[14] They analyzed data from 349 patients who had undergone adjuvant therapy (after curative resection) between 1995 and 2008; 225 patients received adjuvant chemotherapy with an oral fluoropyrimidine alone, while 124 patients received adjuvant chemotherapy plus PSK 3 g/d. Although this was not a randomized trial, baseline characteristics of the patients were well matched. The mean duration of follow-up was 49 months. Three-year recurrence-free survival (RFS) rates were the same for both groups (60% for the PSK group and 62% for the chemotherapy-only group). For MHC expression-negative cases, the 3-year RFS rates were 65% for the PSK group and 50% for the chemotherapy-only group; the difference was not considered significant. For 82 MHC expression-negative patients with lymph node status of pN2 or greater, the RFS rates were 65% for the PSK group and 34% for the chemotherapy-only group-a significant difference with no P value offered. The authors concluded that PSK adjuvant immunotherapy may be effective in MHC class I-negative patients with advanced lymph node metastasis of pN2 or greater.

While the mechanism of action for PSK in general and in colorectal cancer specifically is not clearly defined, the potential activity of PSK as an immunomodulatory adjunct to chemoradiation therapy in rectal cancer has been studied.[15] Thirty patients with stage II or III rectal cancer who were treated with S-1 and external-beam radiation therapy were randomly assigned to receive either the standard regimen or standard regimen plus PSK. A number of cellular and humoral immune parameters were tested. An increase in peripheral blood NK cells after therapy was observed in the PSK-treated group compared with the control group. Immunosuppressive acidic protein (IAP) levels have been reported to be elevated in cancer patients and correlated to cancer progression and prognosis. In the study, a more-marked decrease in IAP level was observed in patients treated with PSK than in those treated in the control group. In addition, cytotoxic T cells increased in the peritumoral mucosa and normal mucosa within the radiation field in the PSK-treated group. The authors of the study concluded that PSK treatment may promote local tissue immunity within the radiation field.

One review included preclinical studies conducted in lung cancer models using either PSK or other T. versicolor preparations.[16] Data from the 15 preclinical studies supported the anticancer effects of PSK by way of immunomodulation and potentiation of immune surveillance. In animal models, direct antitumor effects resulted in reduced tumor growth and metastases.

Human Studies

Gastric cancer

Observational studies

Gastric cancer is the most common malignancy diagnosed in Korea. Investigators in Korea performed a retrospective analysis of survival in patients who received PSK in addition to chemotherapy and in those who received chemotherapy only (control group).[17] Unfortunately, the chemotherapy regimens differed in that the PSK patients were treated with 5-fluorouracil and mitomycin-C (207 patients), while the controls received 5-fluorouracil with doxorubicin -based chemotherapy (103 patients), introducing a potential bias in the interpretation of the results. Patients with all stages of gastric cancer were included in the analysis. Overall, there was no difference between groups in 5-year disease-free survival (DFS) or progression-free survival (PFS) rates. In a subgroup analysis, PSK recipients with stage IB or stage II disease showed a superior 5-year survival (84.4% vs. 67.6%; P = .019), but no significant benefit was observed in patients with higher-stage disease.

Another retrospective analysis of nonrandomized data evaluated 254 patients with gastric carcinoma undergoing curative surgery with postoperative adjuvant treatment in Japan.[18] Researchers compared 139 patients who received chemotherapy alone with 115 patients who received chemotherapy plus PSK. There were no significant differences between groups in patient demographics or tumor characteristics at baseline. There were no differences between groups in 5-year RFS rates (52.7% in the PSK group and 52.7% in the control group) or 5-year OS rates (57.1% in the PSK group and 58.3% in the control group). In a subset analysis of patients with more than seven involved lymph nodes (pN3), the 5-year OS rate was significantly higher in the PSK group (47.8%) than that in the control group (22.8%; P = .0317). Hence, these results contradict the findings from the Korean analysis.

Clinical trials

A study published in 1994 first suggested the clinical benefit of adjuvant PSK for patients who underwent curative resection of gastric cancer in Japan.[19] Investigators randomly assigned 262 patients who had undergone curative gastrectomy to receive either standard treatment with intravenous mitomycin and oral fluorouracil, or chemotherapy plus protein-bound PSK. Patients were monitored for 5 to 7 years. PSK improved both the 5-year DFS rate (70.7% vs. 59.4%; P = .047) and 5-year survival rate (73.0% vs. 60.0%; P = .044), compared with the standard treatment group. Treatment with PSK was well tolerated, with good compliance. The authors concluded that PSK should be added to standard chemotherapy for gastric cancer patients who undergo curative gastrectomy.

A 2007 meta-analysis included 8,009 patients from eight randomized controlled trials (RCTs) of adjuvant PSK in patients after curative resection of gastric cancers:[20] 4,037 patients received PSK with chemotherapy, and 3,972 patients received the same chemotherapy alone. The OS hazard ratio was 0.88 (95% confidence interval [CI], 0.79-0.98; P = .018), indicating improved survival with the addition of PSK, and with no significant heterogeneity between the treatment effects observed in the different studies. The three trials with the best quality supported the findings from the eight studies. The authors concluded that PSK was effective as adjuvant immunotherapy for patients with gastric cancer and suggest that this improvement may well be both statistically and clinically significant.

One other large study not included in this meta-analysis was a Japanese multicenter comparative trial of adjuvant chemotherapy versus adjuvant chemotherapy and PSK involving 751 patients undergoing curative resection, conducted from 1978 to 1981.[21] Patients were randomly assigned to receive either chemotherapy with mitomycin-C plus oral tegafur (also known as futraful) with (n = 377) or without (n = 374) PSK 3 g/d. After reviewing 20 years of data, the investigators stratified patients on the basis of the ratio of their granulocytes to lymphocytes (G/L), believing that G/L ratios above 2.0 would predict responders. The 5-year OS rates were 67.9% in the PSK group and 61.8% in the control group (P = .053). In the subset of 364 patients with G/L ratios above 2.0, 5-year survival rates were 68.7% in the PSK group and 55.4% in the control group (P = .007). Because the G/L ratio was not related to stage, the authors suggested that the G/L ratio may be a host-dependent factor and might be useful to predict who might respond best to adjuvant PSK.

Finally, another small study has been reported since the meta-analysis.[13] Patients received either oral UFT 300 mg/d or UFT plus PSK 3 g/d for at least 1 year after undergoing gastric resection for stage II or stage III gastric cancer. The 3-year survival rate was 62.2% in the 10 patients who received PSK and 12.5% in the 11 patients who received UFT alone (P = .038).

Colorectal cancer

Observational studies

A retrospective study of the survival of 63 patients with colorectal cancer who were older than 70 years and treated with UFT with or without PSK included 24 patients who received UFT plus PSK. The 3-year relapse-free survival rates were 76.2% in the PSK group and 47.8% in the UFT-only group (control), and the 3-year OS rates were 80.8% in the PSK group and 52.8% in the control group.[22]

One study analyzed outcomes from 101 patients at a single institution in Japan who had Dukes B or Dukes C colorectal cancer and were treated with UFT or UFT plus PSK for 24 months after curative surgery. These patients were monitored for up to 10 years after surgery.[23] The 10-year survival was significantly better for patients treated with PSK, with a hazard ratio of 0.3.

Clinical trials

Clinical studies of PSK in colorectal cancer have shown reduction in recurrence and improvement in OS with adjuvant use.

A meta-analysis of randomized, centrally assigned, prospective clinical trials of adjuvant therapy with PSK published between 1980 and 2004 identified three clinical trials that met selection criteria covering 1,094 patients.[24] Combining the data from all three trials, the researchers found that the estimated odds ratio (OR) for 5-year DFS was 0.72 (95% CI, 0.58-0.90; P = .003, favoring PSK), and the OR for 5-year OS was 0.71 (95% CI, 0.55-0.90; P = .006, favoring PSK).

Lung cancer

Clinical trials

Thirty-one reports of 28 studies were included in a systematic review of PSK in lung cancer: 17 preclinical studies, 5 nonrandomized controlled trials, and 6 RCTs.[16] All five nonrandomized controlled trials reported improved median survival with the use of PSK in combination with conventional radiation therapy and/or chemotherapy. PSK 3 g/d with concurrent chemotherapy was used in all RCTs, and all six studies showed benefit for at least one of the endpoints-immune function measures, body weight, performance status, tumor-related symptoms, or survival.

References:

1. Carlson A, Justo A, Hibbett DS: Species delimitation in Trametes: a comparison of ITS, RPB1, RPB2 and TEF1 gene phylogenies. Mycologia 106 (4): 735-45, 2014 Jul-Aug.
2. Ng TB: A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae). Gen Pharmacol 30 (1): 1-4, 1998.
3. Ying J, Mao X, Ma Q, et al.: Icons of Medicinal Fungi from China. Beijing, China: Science Press, 1987.
4. Tsukagoshi S, Hashimoto Y, Fujii G, et al.: Krestin (PSK). Cancer Treat Rev 11 (2): 131-55, 1984.
5. Cui J, Chisti Y: Polysaccharopeptides of Coriolus versicolor: physiological activity, uses, and production. Biotechnol Adv 21 (2): 109-22, 2003.
6. Sakagami H, Aoki T, Simpson A, et al.: Induction of immunopotentiation activity by a protein-bound polysaccharide, PSK (review). Anticancer Res 11 (2): 993-9, 1991 Mar-Apr.
7. Ikuzawa M, Matsunaga K, Nishiyama S, et al.: Fate and distribution of an antitumor protein-bound polysaccharide PSK (Krestin). Int J Immunopharmacol 10 (4): 415-23, 1988.
8. Hoshi H, Saito H, Iijima H, et al.: Anti-protein-bound polysaccharide-K monoclonal antibody binds the active structure and neutralizes direct antitumor action of the compound. Oncol Rep 25 (4): 905-13, 2011.
9. Quayle K, Coy C, Standish L, et al.: The TLR2 agonist in polysaccharide-K is a structurally distinct lipid which acts synergistically with the protein-bound β-glucan. J Nat Med 69 (2): 198-208, 2015.
10. Agatsuma T, Takahashi A, Kabuto C, et al.: Revised structure and stereochemistry of hypothemycin. Chem Pharm Bull (Tokyo) 41 (2): 373-5, 1993. Also available online. Last accessed February 8, 2017.
11. Miller R, Galitsky NM, Duax WL, et al.: Molecular structures of two crystalline forms of the cyclic heptapeptide antibiotic ternatin, cyclo[-beta-OH-D-Leu-D-Ile-(NMe)Ala-(NMe)Leu-Leu-(NMe)Ala-D-(NMe)Ala-]. Int J Pept Protein Res 42 (6): 539-49, 1993.
12. Kono K, Kawaguchi Y, Mizukami Y, et al.: Protein-bound polysaccharide K partially prevents apoptosis of circulating T cells induced by anti-cancer drug S-1 in patients with gastric cancer. Oncology 74 (3-4): 143-9, 2008.
13. Akagi J, Baba H: PSK may suppress CD57(+) T cells to improve survival of advanced gastric cancer patients. Int J Clin Oncol 15 (2): 145-52, 2010.
14. Ito G, Tanaka H, Ohira M, et al.: Correlation between efficacy of PSK postoperative adjuvant immunochemotherapy for gastric cancer and expression of MHC class I. Exp Ther Med 3 (6): 925-930, 2012.
15. Sadahiro S, Suzuki T, Maeda Y, et al.: Effects of preoperative immunochemoradiotherapy and chemoradiotherapy on immune responses in patients with rectal adenocarcinoma. Anticancer Res 30 (3): 993-9, 2010.
16. Fritz H, Kennedy DA, Ishii M, et al.: Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Integr Cancer Ther 14 (3): 201-11, 2015.
17. Choi JH, Kim YB, Lim HY, et al.: 5-fluorouracil, mitomycin-C, and polysaccharide-K adjuvant chemoimmunotherapy for locally advanced gastric cancer: the prognostic significance of frequent perineural invasion. Hepatogastroenterology 54 (73): 290-7, 2007 Jan-Feb.
18. Tanaka H, Muguruma K, Ohira M, et al.: Impact of adjuvant immunochemotherapy using protein-bound polysaccharide-K on overall survival of patients with gastric cancer. Anticancer Res 32 (8): 3427-33, 2012.
19. Nakazato H, Koike A, Saji S, et al.: Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet 343 (8906): 1122-6, 1994.
20. Oba K, Teramukai S, Kobayashi M, et al.: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother 56 (6): 905-11, 2007.
21. Toge T, Yamaguchi Y: Protein-bound polysaccharide increases survival in resected gastric cancer cases stratified with a preoperative granulocyte and lymphocyte count. Oncol Rep 7 (5): 1157-61, 2000 Sep-Oct.
22. Yoshitani S, Takashima S: Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer. Cancer Biother Radiopharm 24 (1): 35-40, 2009.
23. Sakai T, Yamashita Y, Maekawa T, et al.: Immunochemotherapy with PSK and fluoropyrimidines improves long-term prognosis for curatively resected colorectal cancer. Cancer Biother Radiopharm 23 (4): 461-7, 2008.
24. Sakamoto J, Morita S, Oba K, et al.: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother 55 (4): 404-11, 2006.

Changes to This Summary (03 / 02 / 2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Turkey Tail and Polysaccharide-K

Revised text to state that most of the radiolabeled dose is found in expired air, suggesting that the digestion of polysaccharide-K (PSK) may occur in the gut or the metabolism of absorbed PSK may occur somewhere else in the body.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of medicinal mushrooms in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Medicinal Mushrooms are:

• Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)
• John A. Beutler, PhD (National Cancer Institute)
• Patrick J. Mansky, MD (FMH Regional Cancer Therapy Center)
• Jeffrey D. White, MD (National Cancer Institute)

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Medicinal Mushrooms. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/mushrooms-pdq. Accessed <MM/DD/YYYY>. [PMID: 27929633]

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Last Revised: 2017-03-02