Medicinal Mushrooms: Their Role in GI Cancers

MICHAEL TRAUB, ND, DHANP, FABNO 

Medicinal mushrooms play an essential role in the treatment of cancer. In the past decade, the use of mycotherapy has attracted much attention in the efforts to understand various benefits and the possible mechanisms through which they influence cancer prevention, carcinogenesis, and anti-cancer therapy. A relatively large number of studies have indicated that mushrooms affect cancer via multiple pathways. Further studies have suggested that mushrooms enhance the efficacy of anti-cancer agents. This article aims to provide a useful overview of the available human studies on the prevention and treatment of cancers of the gastrointestinal (GI) tract using medicinal mushrooms; the article will highlight gastric, colorectal, and liver cancers.  

Trametes versicolor 

Trametes versicolor, formerly known as Coriolus versicolor (common name, turkey tail), is the most widely researched of all medicinal mushrooms. The common name is based on the fruiting bodies’ banding pattern, which resembles that of a strutting turkey’s tail. The colors in these bands can vary, depending on genetics and environment. Most bands are various shades of brown, and alternate with white-to-tan bands. Additional hues can be found on other bands, eg, orange, blue, and maroon. Because this mushroom can be strikingly beautiful, it is often easily found. Trametes versicolor is widely distributed throughout the United States and in most other countries. Its medicinal value as part of traditional Chinese medicine dates back for at least 2000 years and includes general health-promoting effects, including endurance and longevity.  

Trametes contains polysaccharide K (PSK) and polysaccharopeptides (PSP). PSK boosts natural killer (NK) cell production, improves side effects from chemotherapy and radiation therapy, and enhances survival in cancers of the stomach, colon, and liver in combination with conventional treatments.^1-4 PSP enhances immune status in patients with cancer of the stomach or esophagus when used as adjuvant to chemotherapy.⁵ 

Gastric Cancer 

Observational Studies 

Gastric cancer is the third-leading cause of cancer-related mortality worldwide and the most common malignancy in Korea.⁶ Korean investigators published a retrospective analysis of survival in patients with all stages of gastric cancer who received PSK in addition to chemotherapy or received chemotherapy only (control group).⁷  

Unfortunately, the chemotherapy regimens differed in that the 207 PSK patients were treated with 5-fluorouracil and mitomycin-C, while the 103 controls received 5-fluorouracil with doxorubicin-based chemotherapy – a factor that introduced bias in the interpretation of the results. 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=0.019); however, no significant benefit was observed in patients with more advanced disease.⁷  

Another retrospective analysis of non-randomized data evaluated 254 Japanese patients with gastric cancer undergoing curative surgery with postoperative adjuvant treatment.⁸ The investigators compared 138 patients who received chemotherapy alone (controls) with 115 patients who received chemotherapy plus PSK. There were no differences between groups in 5-year relapse-free survival (RFS) rates (52.7% in the PSK group vs 52.7% in the control group) or 5-year overall survival (OS) rate (57.1% in the PSK group vs 58.3% in the control group). However, in a subset analysis of patients with more than 7 involved lymph nodes, the 5-year OS rate was significantly higher in the PSK group (47.8%) than that in the control group (22.8%; p=0.0317).⁸ Hence, these results contradict the findings from the Korean study. 

Lentinula edodes 

Lentinula edodes is the most popular edible mushroom worldwide, and is the second-largest cultivated mushroom. It is known in China as “Xianggu” and as “shiitake” in Japan.⁹ Lentinan is a polysaccharide in Lentinula edodes, the extract of which has been approved as an intravenous biological response modulator in both Japan and China for cancer treatment since the 1980s.⁹ In a systematic review, more than 9474 lentinan-associated treatment cases were evaluated and then summarized from 135 studies in China from 2004-2016, including gastric, colorectal, pancreatic, and duodenal cancers. Results showed clear beneficial effects of lentinan on quality of life and the efficacy of chemotherapy and radiation therapy.⁹  

Lentinan has been used along with oral fluoropyrimidines in gastric cancer patients to improve their overall survival. A retrospective study examined 138 patients with metastatic gastric cancer who were receiving chemotherapy in a Japanese hospital from 2010 to 2015. Twelve patients with liver metastases were treated with lentinan in combination with chemotherapy. Five of the 12 patients (42%) receiving lentinan plus chemotherapy showed an objective response to treatment, and the disease rate was controlled in 10 of the 12 (83%). Those who responded to the treatment experienced longer survival, with a median survival of 407 days (95% CI: 207-700 days).¹⁰  

A meta-analysis was conducted that examined data from patients with advanced gastric cancer who received standard chemotherapy with or without lentinan. In terms of survival among patients with advanced gastric cancer, the addition of lentinan to standard chemotherapy was found to offer a significant advantage compared to chemotherapy alone.¹¹  

Clinical Trials 

A 1994 Lancet study first suggested the benefit of adjuvant PSK for patients who underwent curative resection of gastric cancer in Japan. 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.¹² Patients were followed for 5-7 years. As compared with the standard treatment group, PSK significantly improved both the 5-year DFS rate (70.7% vs 59.4%; p=0.047) and 5-year survival rate (73.0% vs 60.0%; p=0.044). The authors concluded that PSK should be added to standard chemotherapy for gastric cancer patients who undergo curative gastrectomy.¹²  

A 2007 meta-analysis examined 8009 patients from 8 randomized controlled trials (RCTs) of adjuvant PSK in patients after curative resection of gastric cancer.¹³ A total of 4037 patients received PSK with chemotherapy, while 3972 patients received the same chemotherapy alone. The OS hazard ratio was 0.88 (95% CI, 0.79-0.98; p=0.018), indicating significantly improved survival with the addition of PSK. The 3 highest-quality trials supported the findings from the 8 studies. The authors concluded that PSK was effective as adjuvant immunotherapy for patients with gastric cancer, and suggested that “this improvement may well be both statistically and clinically significant.”¹³  

A large study not included in this meta-analysis was a Japanese multicenter trial, conducted from 1978 to 1981, which compared the effects of adjuvant chemotherapy plus PSK, vs adjuvant chemotherapy alone, in 751 patients undergoing curative resection.¹⁴ Patients were randomly assigned to receive either chemotherapy with mitomycin-C plus oral tegafur 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=0.053). In the subset of 364 patients with G/L ratios above 2.0, 5-year survival rates were significantly better in the PSK group (68.7%) than in the control group (55.4%; p=0.007). 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 possibly useful for predicting who might respond best to adjuvant PSK.¹⁴  

Another small study has been reported since the meta-analysis discussed above. Patients received either oral tegafur and uracil (UFT) (300 mg/d) or UFT plus PSK (3 g/d) for at least 1 year after undergoing gastric resection for stage II or III gastric cancer.¹⁵ The 3-year survival rate was significantly higher (62.2%) in the 10 patients who received PSK compared to the 12.5% survival rate in the 11 patients who received UFT alone (p=0.038). 

In contrast to the aforementioned studies, a randomized trial investigating lentinan in 309 patients with unresectable or recurrent gastric cancer in combination with standard chemotherapy found no efficacy of lentinan. Moreover, time-to-treatment failure was significantly worse when lentinan was combined with chemotherapy, as compared to chemotherapy alone.¹⁶  

Colorectal Cancer 

Observational Studies 

A retrospective study of the survival of 63 elderly patients (>70 years) with resected colorectal cancer and treated with UFT included 24 patients who received PSK in addition to the UFT.¹⁷ The 3-year relapse-free survival rates were 76.2% in the PSK group and 47.8% in the UFT-only group (controls), and the 3-year OS rates were 80.8% in the PSK group and 52.8% in the control group. In a subset analysis of those patients whose tumors were in the colon (p=0.016) and whose preoperative lymphocyte percentage was less than 18.7% (p=0.017), RFS was significantly superior in the group receiving PSK.¹⁷  

Another study, at a single institution in Japan, analyzed outcomes from 101 patients who had Stage II or III 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.¹⁸ The 10-year survival was significantly better for patients treated with UFT and PSK (81.9%) as compared with patients treated with UFT only (50.6%), with a hazard ratio of 0.3. 

Clinical Trials 

Clinical trials of adjuvant PSK treatment for colorectal cancer have shown reduction in recurrence and improvement in OS. A meta-analysis of 3 RCTs (including 1094 patients) examined the effects of adjuvant therapy with PSK (3 g/d of hot water extract).¹⁹ Combining the data from all 3 trials, the researchers found that adjuvant PSK treatment improved both 5-year OS and 5-year DFS, as compared with treatment using standard chemotherapy alone. In the PSK group, the estimated odds ratio (OR) for 5-year DFS was 0.72 (95% CI, 0.58-0.90; p=0.003); for 5-year OS, the OR was 0.71 (95% CI, 0.55-0.90; p=0.006).¹⁹  

Ganoderma lucidum 

Ganoderma lucidum, commonly known as reishi, is a very popular medicinal mushroom that represented a $2.5 billion industry in the United States in 2015.²⁰ A 2012 Cochrane review of RCTs examined the use of Ganoderma as cancer treatment in all types and stages of cancer. Results demonstrated that the mushroom had a positive impact on quality of life, as significantly more subjects achieved an increase in performance status after taking Ganoderma, as compared to control groups (p<0.01).²¹ The meta-analysis results showed that patients receiving Ganoderma alongside chemotherapy/radiotherapy were 50% more likely to respond positively, as compared to chemotherapy/radiotherapy alone (p=0.02). Ganoderma treatment alone did not demonstrate the same regression rate as that seen in combined therapy. Ganoderma significantly increased the percentage of CD3, CD4 and CD8 cells, and marginally increased white blood cells and NK cell activity.²¹  

In an open-label clinical trial, 47 patients with advanced colorectal cancer were administered Ganoderma, 5.4 g/d for 12 weeks.²² Results showed that, compared to baseline, 41 of the 47 patients had increased mitogenic reactivity, increased counts of CD3, CD4, CD8 and CD56 lymphocytes, and increased NK cell activity. However, none of these responses reached statistical significance. In a population of patients with advanced cancer, these results are not surprising.²²   

Colorectal Cancer Prevention 

Japanese investigators studied the effects of a water-soluble extract from a cultured medium of G lucidum mycelia (MAK) in patients with colorectal adenomas.²³ Investigators randomized 123 patients in the MAK treatment group and 102 controls. The treatment group was administered 1.5 g/d of MAK for 12 months, after which both groups underwent repeat colonoscopy. The number of adenomas increased in the control group (+0.66 +/- 0.10) and decreased in the treated group (-0.42 +/- 0.10) (p<0.01). The total size of adenomas increased in the control group (1.73 +/- 0.28 mm) in the control group, whereas it decreased in the treated group (-1.40 +/- 0.64 mm) (p<0.01). These results suggest that MAK may suppress the development of premalignant colorectal adenomas.²³ 

Hepatocellular Carcinoma 

Observational Studies 

Active hexose correlated compound (AHCC) is a generic term to describe a plant polysaccharide extracted from a liquid culture of mycelia of Lentinula edodes. In a mouse study, AHCC was shown to have immunostimulating activity, anticancer activity, cancer-preventive actions, and the ability to prevent side effects during cancer chemotherapy.²⁴  

A total of 269 consecutive patients with resected hepatocellular carcinoma (HCC) were studied from 1992 to 2001. Of these patients, 113 received oral AHCC on a daily basis. Compared to the control group, the AHCC group had a significantly longer recurrence-free period (HR, 0.639; 95% CI, 0.429-0.952; p=0.0277) and an increased OS rate (HR, 0.421; 95% CI, 0.253-0.701; p=0.0009). Results indicated that AHCC has the ability improve the prognosis of HCC patients after resection.²⁵  

Ophiocordyceps sinensis 

Ophiocordyceps sinensis is generally referred to as cordyceps or caterpillar fungus. Cordyceps is not a mushroom, but rather a fungus. It is known to parasitize the larvae of ghost moths and to produce a fruiting body. Cordyceps will germinate in the living larva, kill it, and mummify it. At this point, the stalk-like fruiting body surfaces from the corpse.  

Cordyceps, in combination with 12 other traditional Chinese medicines, has been shown to prolong survival in patients with HCC.²⁶ A total of 101 HCC patients were treated for a median of 13.4 months with adjunctive naturopathic therapy including cordyceps. Results demonstrated a significant correlation between survival and the number of natural agents administered: Patients treated with 4 or more agents survived significantly longer (40.2 months), as compared to patients treated with 1-3 agents (6.4 months). The greatest survival benefit was observed in patients who were treated with at least 4 agents that included cordyceps.²⁶ 

Agaricus blazei Murill  

The mushroom Agaricus blazei Murill (ABM) contains agaratines, which were found to be carcinogenic in mice.²⁷ Raw Agaricus mushroom species may thus possibly expose consumers to low-level carcinogens. All mushrooms should therefore be heated in order to destroy toxins and make them more digestible as well. Agaricus has also been reported to induce hepatoxicity in 3 individuals.²⁸  

On the other hand, ABM can act as an enhancer in cancer treatment by sensitizing doxorubicin (Dox)-mediated apoptotic signaling via inhibition of NFκB activity. ABM, when combined with low doses of Dox, has the potential to provide more efficient therapeutic effects against drug-resistant HCC.²⁹  

Conclusion 

Evidence of safety and efficacy of medicinal mushroom use in gastrointestinal cancers has been accumulating rapidly over the past decade, and more well-designed clinical trials are to be expected. Insofar as the vast majority of the data has derived from Asia, more data should be collected in other populations as well. 

References: 

1. Lu H, Yang Y, Gad E, et al. TLR2 agonist PSK activates human NK cells and enhances the antitumor effect of HER2-targeted monoclonal antibody therapy. Clin Cancer Res. 2011;17(21):6742-6753. 
2. Kariya Y, Inoue N, Kihara T, et al. Activation of human natural killer cells by the protein-bound polysaccharide PSK independently of interferon and interleukin 2. Immunol Lett. 1992;31(3):241-245.  
3. Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res. 2002;22(3):1737-1754. 
4. Ogoshi K, Satou H, Isono K, et al. Immunotherapy for esophageal cancer. A randomized trial in combination with radiotherapy and radiochemotherapy. Cooperative Study Group for Esophageal Cancer in Japan. Am J Clin Oncol. 1995;18(3):216-222.  
5. Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5(1):4-27.  
6. Jung KW, Park S, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality and survival in 2006-2007. J Korean Med Sci. 2010;25(8):1113-1121. 
7. 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. 2007;54(73):290-297. 
8. 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. 2012;32(8):3427-3433. 
9. Zhang M, Zhang Y, Zhang L, Tian Q. Mushroom polysaccharide lentinan for treating different types of cancers: A review of 12 years clinical studies in China. Prog Mol Biol Transl Sci. 2019;163:297-328. 
10. Ina K, Furuta R, Kataoka T, et al. Chemo-Immunotherapy Using Lentinan for the Treatment of Gastric Cancer and Liver Metastases. Med Sci (Basel). 2016;4(2):8.  
11. Oba K, Kobayashi M, Matsui T, et al. Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Anticancer Res. 2009;29(7):2739-2745. 
12. 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. 1994;343(8906):1122-1126. 
13. 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. 2007;56(6):905-911. 
14. Toge T, Yamaguchi Y. Protein-bound polysaccharide increases survival in resected gastric cancer cases stratified with a preoperative granulocyte and lymphocyte count. Oncol Rep. 2000;7(5):1157-1161. 
15. Akagi J, Baba H. PSK may suppress CD57(+) T cells to improve survival of advanced gastric cancer patients. Int J Clin Oncol. 2010;15(2):145-152. 
16. Yoshino S, Nishikawa K, Morita S, et al. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016;65:164-171. 
17. Yoshitani S, Takashima S. Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer. Cancer Biother Radiopharm. 2009;24(1):35-40. 
18. 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. 2008;23(4):461-467. 
19. 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. 2006;55(4):404-411. 
20. Bishop KS, Kao CH, Xu Y, et al. From 2000years of Ganoderma lucidum to recent developments in nutraceuticals. Phytochemistry. 2015;114:56-65. 
21. Jin X, Ruiz Bequerie J, Sze DM, Chan GC. Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane Database Syst Rev. 2012;(6):6CD007731. 
22. Chen X, Hu ZP, Yang XX, et al. Monitoring of immune response to a herbal immune-modulator in patients with advanced colorectal cancer. Int Immunopharmacol. 2006;6(3):499-508. 
23. Oka S, Tanaka S, Yoshida S, et al. A water-soluble extract from culture medium of Ganoderma lucidum mycelia suppresses the development of colorectal adenomas. Hiroshima J Med Sci. 2010;59(1):1-6. 
24. Shigama K, Nakaya A, Wakame K, et al. Alleviating effect of active hexose correlated compound (AHCC) for anticancer drug-induced side effects in non-tumor-bearing mice. J Exp Ther Oncol. 2009;8(1):43-51. 
25. Matsui K, Uhara J, Satoi S, et al. Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study. J Hepatol. 2002;37(1):78-86. 
26. Niwa Y, Matsuura H, Murakami M, et al. Evidence that naturopathic therapy including Cordyceps prolongs survival of patients with hepatocellular carcinoma. Integr Cancer Ther. 2013;12(1):50-68. 
27. Hashida C, Hayashi K, Jie L, et al. [Quantities of agaritine in mushrooms (Agaricus bisporus) and the carcinogenicity of mushroom methanol extracts on the mouse bladder epithelium]. Nihon Koshu Eisei Zasshi. 1990;37(6):400-405. 
28. Mukai H, Watanabe T, Ando M, Katsumata N. An alternative medicine, Agaricus blazei, may have induced severe hepatic dysfunction in cancer patients. Jpn J Clin Oncol. 2006;36(12):808-810.  
29.  Lee JS, Hong EK.  Agaricus blazei Murill enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells by NFκB-mediated increase of intracellular doxorubicin accumulation. Int J Oncol. 2011;38(2):401-408. 

Michael Traub, ND, DHANP, FABNO has practiced in Hawaii since 1985. Dr. Traub is Past-President of the American Association of Naturopathic Physicians (AANP) and received the AANP’s naturopathic “Physician of the Year” award in 2006. He is board-certified in Naturopathic Oncology and has served on the boards of the Oncology Association of Naturopathic Physicians and the American Board of Naturopathic Oncology. He is a contributing author for the Textbook of Naturopathic Oncology.