Survival Rates in Gastric Cancer Patients Using Lentinan

Ina K, Furuta R, Kataoka T, et al. Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy. World J Clin Oncol. 2011;2(10):339-343.

 

Retrospective comparative effectiveness cohort study design, between S-1 chemotherapy alone and S-1 chemotherapy with lentinan

 

68 patients receiving oral fluoropyrimidine S-1-based chemotherapy at Nagoya Memorial Hospital between August 2004 and July 2010 with pathologically proven inoperable gastric cancer and at least 1 measurable lesion. Age range restricted to less than 86 years old. Those with severe hepatic, renal, or bone marrow impairment were excluded. Patients with multiple cancers, those with an Eastern Cooperative Oncology Group performance status of 4, those with brain metastases, and those whose outcome were unclear were also excluded. The chemotherapy alone group comprised 37 cases (29 men/8 women) and the chemo-immunotherapy with lentinan comprised 31 cases (19 men/12 women).

 

In this study, the S-1-based chemotherapy used included S-1 alone, S-1/paclitaxel, S-1/cisplatin, and paclitaxel with S-1 plus cisplatin (PSC triple therapy). S-1 was given orally twice daily based on the patient’s body surface area (BSA), i.e. BSA < 1.25 m2, 40 mg; 1.25-1.50 m2, 50 mg; and BSA > 1.50 m2, 60 mg for 2 wk followed by either 1 wk rest for patients who received S-1 alone or 2 wk rest for those who received combination therapy. For the S-1/cisplatin therapy, cisplatin at a dose of 70 mg/m2 was administered by continuous infusion for 24 h on day 8. For the S-1/ paclitaxel therapy, paclitaxel at a dose of 50 mg/m2 was administered by a 2-h infusion on days 1 and 15. For the PSC triple therapy, paclitaxel at a dose of 120 mg/m2 was administered by a 2-h infusion on day 1 and cisplatin at a dose of 60 mg/m2 by continuous infusion for 24 h on day 14. Doses were adjusted at the initiation of subsequent cycles if severe toxicity (grade 3-4) was present; administration of S-1 was discontinued and then resumed at a reduced dose (10 mg/m2 per day) and the dose of paclitaxel was reduced by 25% in the next cycle if toxicity was resolved. Administration of cisplatin was postponed until toxicity resolved; the maximum duration of postponement was no more than 2 wk. In the lentinan-treated group, 2 mg/body of lentinan was intravenously administered for 30 min every 2 or 3 wk. OS was calculated from the start of S-1-based chemotherapy until death or the most recent follow-up day. 

 

Survival, side effects, and the ratio of granulocytes/lymphocytes (G/L ratio) were compared between the 2 groups. 

 

Median overall survival was significantly longer in the group receiving chemo-immunotherapy than in the group receiving chemotherapy alone (689 d [95% CI: 431–2,339 d] vs 565 d [95% CI: 323–662 d], P=0.0406]. In addition, the G/L ratio in patients who received lentinan was maintained around or below 2, which was significantly lower than that in patients who received chemotherapy alone (P<0.001). 

 

These findings published by Ina et al suggest that chemo-immunotherapy with lentinan provides a survival advantage in patients with inoperable gastric cancer. This is the most recent investigation of lentinan used for this purpose in a number of studies going back to at least 1983, where it was reported that it improved survival, immune response, and hematological measures in advanced or recurrent gastric, colorectal, and breast carcinomas.¹

 

Beta-glucan is a polysaccharide in the form of fiber and the main element of fiber in grains such as barley, oats, yeast, and mushrooms. β-glucan is present in natural yeast and mushrooms mainly as β-1,3-glucan or β-1,6-glucan, and as β-1,3-glucan and β-1,4-glucan in oats and barley. Lentinan is β-1, 3-glucan extract of Lentinus edodes, otherwise known as Shiitake mushroom. Lentinan acts in the following manner: 1) promotes the secretion of cytokines such as TNF-α and IL-1-β, which bind to glucan receptors in macrophage and neutrophils that form part of the nonspecific immune system, 2) suppresses the secretion of superoxide anion and hydrogen peroxide, and 3) increases the activity of natural killer and lymphokine-activated killer (LAK) cells, which contribute to their germicidal and anticarcinogenic effects.²

 

Many studies have examined beta-glucan's lipid-lowering, blood sugar reduction, weight reduction, immune modulator, and anticarcinogenic effects. A comprehensive review on beta glucan was published in 2006.³

 

There have been numerous case reports and more than 20 randomized controlled studies on the use of β-glucan in cancer treatment, primarily carried out in Japan, where lentinan is used with chemotherapy, similar to how Viscum album is used with chemotherapy in Germany.

 

The study by Ina et al employed lentinan 2 mg/body intravenously for 30 minutes every 2 or 3 weeks. Concern about the ineffectiveness of lentinan, a polysaccharide of high molecular weight (400,000–1,000,000 daltons) when administered orally was resolved in a 2005 publication.⁴ Beta glucan particle size of 100–200 microns in aqueous solution is not well absorbed through the gastrointestinal mucosa, which impairs its immunostimulating potency and inhibits its ability to reduce the side effects of chemotherapeutic agents and improve patient’s quality of life. Using nanotechnology, Hamuro developed Mitherapist, a finely dispersed form of β-glucan containing 15 mg/dl lentinan. With a particle size of 0.2 microns, it readily passes through the mucosal barrier. It was found in randomized, double-blind clinical testing that Mitherapist was effective in reducing the side effects of chemotherapeutic agents such as TS-1, Gemzar, and CDDP and greatly improved patient’s quality of life.⁴ Lentinan and Mitherapist were developed and are produced by Ajinomoto Pharmaceuticals Co., Ltd. in Japan.

 

Reports and studies of β-glucan in inoperable or recurrent stomach cancer have all reported extension of survival time. Positive results have also been reported in uterine and metastatic prostate cancer in most cases.³ Lentinan should be widely accepted as a treatment for unresectable or recurrent advanced gastric cancer. Chemo-immunotherapy with an S-1 based regimen and letninan might be a candidate for the standard treatment of advanced gastric cancer. In Japan, a phase III study comparing therapy with S-1/lentinan and S-1 alone is now underway.

 

Overall, yeast glucan administered to cancer patients can enhance the effect of anticancer chemotherapy or radiation therapy and has positive effects on the survival and quality of life of cancer patients. However, as stated above, most studies were carried out in one country only (ie, Japan) and by similar research groups. Given that subjects from a single country cannot provide an adequate sample and that similar research groups are likely to make the same types of error (if any were made), it would be wise to confirm these results by other researchers in other countries.

 

A trend toward integration of immunopotentiating agents with cancer surgery, chemotherapy, and radiation therapy is fairly advanced in Japan, China, and Germany. In North America, a more proactive approach to cancer management is in its early stages. The availability of good clinical evidence supporting medicinal mushrooms should help to generate improved cancer survival rates. With their capacity to mobilize the immune system against tumors and metastases, while also reducing the side effects of chemotherapy and radiation therapy, medicinal mushroom preparations such as lentinan should offer a valuable option.