Category Archives: Clinical Trials

Clinical Potential of Biological Response Modifiers Combined with Chemotherapy for Gastric Cancer

Masahiko Shibata Takeshi Nezu Shigeru Fujisaki Katsuyuki Andou
Ryouichi Tomita Masahiro Fukuzawa

The most effective treatment for gastric cancer is complete surgical resection with lymphadenectomy. However, a number of patients experience recurrence of the cancer even after curative surgery. This review focuses on comparative trials studying the use of adjuvant therapy with chemotherapy plus immunotherapy in the treatment of patients with curatively resected gastric cancer. Preoperative and intraperitoneal therapy, and therapy for advanced or recurrent gastric cancer are also discussed. At present, some subset analyses of adjuvant trials have shown favorable results suggesting that the biological response modifiers (BRMs), PSK or OK-432, add a benefit to chemotherapy. For advanced gastric cancer, although gastric cancer cells are generally not very sensitive to most of the currently available chemotherapeutic agents, it has been reported that biochemical modulation with treatments including low-dose cisplatin + 5-FU (fluorouracil) have high response rates and exert an immunomodulatory effect especially when used in combination with BRMs. The impact of splenectomy and some of the
promising newly developed drugs are discussed.

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Clinical Experience in the Use of PSP

W.C. Xue and T.F. Liu

There is no really effective treatment for moderate and advanced stages of esophageal carcinoma. Although surgery for the earlier cases has been able to give a 5 years survival rate of 28.7%, such operable cases are relatively few. By far the greater majority are already in stage III to IV when first seen in the clinic, and radiotherapy alone in these cases has given a 5 years survival rate of only 8-14%. In order to improve treatment results, a variety of chemotherapeutic agents have been used in combination surgery, but so far no really effective drug has been found.
The drug PSP (polysaccharide-peptide of Coriolus versicolor) has been discovered and produced by Professor Qing-yao Yang of. It is a new anti-cancer and immuno-regulatory drug, similar to PSK (Krestin) but the effective component has been found to be larger than PSK. Experimental data has proved these properties of PSP, and in vitro as well as in vivo studies have all proved that PSP is superior to PSK. Of course, as is the case with all new drugs, the ultimate proof of its value will have to be shown by clinical application.
Data on Krestin suggest that this family of drugs when used in combination with radiotherapy, there might be an increase of the biological effects of radiation. To do a pilot study on such a possibility, the authors have treated 41 moderate to advanced cases of esophageal carcinoma with a combination of PSP and radiotherapy.

Antitumor effects of residual tumor after cryoablation: the combined effect of residual tumor and a protein-bound polysaccharide on multiple liver metastases in a murine model

Masato Urano, Chihiro Tanaka, Yasuyuki Sugiyama, Kiichi Miya, and Shigetoyo Saji*

Cryoablation is a low-invasive surgical treatment for malignant tumors. It may induce an immunological response leading to the eradication of distant metastases or alternatively it might promote the growth of residual tumors. In this paper we confirm the occurrence of both phenomena and we describe the preventive effect of a protein-bound polysaccharide preparation. Metastatic liver tumors were produced in BALB/c mice by the intrasplenic inoculation of colon 26 cells and cryoablation was carried out usingliquid nitrogen ()170C) applied by a contact method. The value of combiningcryoablation with administration of the polysaccharide preparation in the prevention of growth of residual tumors was investigated. It was shown that the number of metastatic liver nodules and the size of the primary tumor at the site of inoculation in the spleen were significantly lower when the volume that was frozen was small. The production by splenocytes of the tumor necrosis factor TNF-a, interferon INF-c, and the interleukins IL-4 and IL-10 increased significantly after freezing and thawing of the tumor tissue. The polysaccharide treatment significantly reduced the production of IL-4 and IL-10 followingcryoablation; the production of TNF-a and INF-c was slightly promoted; the natural killer and cytotoxic T-cell activities of splenocytes were slightly enhanced. It was concluded that the polysaccharide preparation was beneficial by suppressing IL-4 and IL-10 production and might inhibit the growth of residual tumor that is sometimes induced by large-volume cryoablation.

Alternating immunotherapy of advanced gastric carcinoma: A randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carabzilquinone (CQ) and PSK (Krestin) or carbazilquinone alone.  Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses.  In each course of 6 weeks, CQ was administered on day 0, 8, and 15.  In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2g/m^2/day from the day of the third CQ administration for consecutive 4 weeks.  Estimated survival rate and cumulative survival curve were compared untilizing the data up to 7 years after the operation.  There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients survived significantly longer when treated with the combination of CQ and PSK.  Neither in more advanced cases nor in cancers of early stages, the addition of PSK provided an additive effect.  The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.?

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Evaluation of widely consumed botanicals as immunological adjuvants.

Ragupathi G, Yeung KS, Leung PC, Lee M, Lau CB, Vickers A, Hood C, Deng G, Cheung NK, Cassileth B, Livingston P.

Laboratory of Tumor Vaccinology, Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.


BACKGROUND: Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with seven botanicals purported to have immune stimulant effects.

METHODS: Groups of 5-10 mice were immunized with globo H-KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. three times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested: (1) H-48 (Honso USA Co.), (2) Coriolus versicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co. Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast beta-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semisynthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH.

RESULTS: Consistent significant adjuvant activity was observed after s.c. vaccination with the Coriolus extracts (especially PSK), a 95% ethanol extract of Astragalus and yeast beta-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H-48 or Echinacea extracts or the Astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast beta-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in Astragalus, it had no impact on Coriolus where the 90% ethanol precipitate and solute were equally active.

CONCLUSIONS: Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and Astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components.

PMID: 18640165 [PubMed – indexed for MEDLINE]PMCID: PMC2565601

Alternating immunochemotherapy of advanced gastric carcinoma: a randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection.

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ) and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m2/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m2/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S1 + S2(N1-2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (greater than S3 or greater than N3) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.

Adjuvant therapy with protein-bound polysaccharide K and tegafur uracil in patients with stage II or III colorectal cancer: randomized, controlled trial.

PURPOSE: Intravenous fluorouracil and leucovorin for six to eight months is currently a standard adjuvant treatment for Stage III colon cancer; however, this regimen is complex, inconvenient, and has a high intolerability. Adjuvant chemotherapies are claimed for objective response rates with an acceptable safety profile and complexity. We investigated the benefits of oral protein-bound polysaccharide K added to oral tegafur/uracil on curatively resected Stage II or III colorectal cancer. METHODS: We prospectively randomized 207 patients to treatments of either oral 3.0 g protein-bound polysaccharide K plus 300 mg tegafur/uracil or 300 mg tegafur/uracil alone for two years following 12 mg/m2 and 8 mg/m2 mitomycin treatment on postoperative Days 1 and 2, respectively. The primary end points were disease-free and overall survival, and recurrence rates. RESULTS: Three (1.4 percent) patients were declared ineligible, and three patients did not start treatment. In total, 201 patients were analyzed. The three-year, disease-free survival rate was 80.6 percent (standard error = 3.4 percent) in the protein-bound polysaccharide K group (P = 0.02) compared with 68.7 percent (SE = 5.7 percent) in the control group after a median follow-up of 3.7 years. The estimated relative risk of recurrence in the control group was 1.87 (95 percent confidence interval, 1.10-3.20) at three years. The three-year, overall survival rate was 87.3 percent (standard error = 2.9 percent) in the protein-bound polysaccharide K group and 80.6 percent (standard error = 4.8 percent) in the control group (P = 0.24). The three-year, overall survival rate in 80 pathological TNM Stage III patients was 83.0 percent (standard error = 5.2 percent) in the protein-bound polysaccharide K group and 59.3 percent (standard error = 9.5 percent) in the control group (P = 0.02). Protein-bound polysaccharide K prevented distant metastases (P = 0.05), particularly lung metastases (P = 0.01). The incidence of adverse effects was minimal, and compliance was good. CONCLUSION: Adjuvant therapy using a combination of oral protein-bound polysaccharide K and tegafur/uracil is highly effective in preventing the recurrence of colorectal cancer in Stage II or III patients, and increases overall survival in pathological TNM Stage III. These results will be a sufficient proof to conduct a larger study to compare tegafur/uracil/protein-bound polysaccharide K with 5-fluorouracil/leucovorin.

Mushroom immunutrition in Chronic Fatigue Immune Dysfunction Syndrome

In the recently published edition of the Journal of Integrated Medicine (Online version), Dr. Jean Monro of the Breakspear Hospital outlines the impact of Coriolus versicolor supplementation as immunonutrition in thirty-six (36) Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) patients over a six week period.

The 36 patients were selected on the basis of international criteria for the diagnosis of CFIDS. Ages ranged from 17 years to 83 years and there was a female-to-male ratio of 2:1. In addition, the patients had a combination of high antibody levels to Epstein Barr virus (EBV) and/or Herpes Simplex 6 virus (HHV6) and/or Cytomegalovirus. (CMV).

Patients were given Coriolus versicolor (non-extracted) 6 tablets daily for 15 days (3 g/day), followed by 3 tablets daily for 45 days (1.5 g/day). Immune parameters were measured before and after the sixty (60) day supplementation period.

Results were noted in two areas:

1) Natural Killer Cells–before treatment the average NK cell level was average=129.64/mm3. After treatment this had increased to 175/mm3, an increase of 35%.

2) T cells (CD3 CD26)–there was increased activation in 66% of patients and T cell depression in 22% of patients. T cell level was unchanged in 11% of the patients.


Supplementation with non-extracted Coriolus versicolor showed improvements in both immune parameters and viral levels in the majority of the thirty-six (36) CFIDS patients, indicating that Coriolus versicolor supplementation has the potential to play a significant role in the treatment of CFIDS.

Clinical Trial Results Show Proof-of-Concept For Use Of Coriolus Versicolor As Immunonutrition In HPV Patients With Cervical Lesions (LSIL)

(Medical News Today – 4/29/2008) The results of a year long clinical trial examining the effects of mushroom supplementation in patients with Human Papillomavirus (HPV) have recently been presented at congress. Dr. Jose Silva Couto and Dr. Daniel Pereira da Silva of the Cervical Pathology Unit of the Portuguese Institute of Oncology in Coimbra, Portugal presented their findings at the 20th European Congress of Obstetrics and Gynaecology, in Lisbon Portugal. This study provides a promising set of results and demonstrates proof-of concept for the question as to whether immunonutrition supplements can be successfully used to improve HPV status in patients.

The poster presentation detailed the results of the evaluation of the Efficacy of Coriolus versicolor Supplementation in patients infected with HPV with low-grade squamous intraepthithelial lesions (LSIL). The Coriolus versicolor mushroom supplied for the study was produced by Mycology Research Laboratories Ltd in tablet form (500 mg/tablet).

Dr. Silva Couto et al. found that Coriolus versicolor supplementation over a period of one year substantially increased regression of the dysplasia (LSIL) and induced clearance of the high risk sub-types of the HPV virus responsible for cervical cancer.

a) Coriolus versicolor supplementation demonstrated a 72% regression rate in LSIL lesions compared to 47.5% without supplementation.

b) Coriolus versicolor supplementation demonstrated a 90% regression rate in the high risk HPV virus sub-types compared to 8.5% without supplementation.

Study Design

The year long study was funded by Mycology Research Laboratories Ltd. The Portuguese pharmaceutical firm Aneid-Produtos Farmacêuticos Lda acted as collaborative partners.

Forty-three (43) patients with HPV Lesions (LSIL) were divided into two groups:

– A Control group (21 patients) who did not receive any treatment

– A treatment group (22 patients) who each received Coriolus versicolor supplementation for a period of one year (6 tablets/day i.e. 3g/day)

Protocol Design

At first observation, patients were examined with colposcopy, biopsy and HPV tipification (hybrid capture). Cervical cytology exams (Pap smear tests) determined the patients’ LSIL status and this was confirmed through colposcopy and biopsy.

Four months after the first observations, colposcopy and cervical cytology was again carried out on all patients. At the same time, there was an evaluation of the possible side effects from Coriolus supplementation.

After one year, (at the end of the supplementation period), colposcopy, cervical cytology and HPV typing were carried out on all patients.

Success Parameters

The authors measured the efficacy of Coriolus supplementation in LSIL patients in terms of the evolution of HPV status from High Risk HPV+ status to High Risk HPV- status. High Risk HPV, refers to certain strains of HPV that are known to be associated with causing cervical cancer, such strains include HPV 16, 18, 31 and 45. The persistence of cervical lesions as measured by colposcopy and cytology was also determined.

Study Population

Out of the 43 patients enrolled, 39 completed the trial. Of the four (4) who did not complete the trial, 1 patient left the country and 3 discontinued supplementation due to mild side-effects. The side-effects were not serious and did not warrant further medical intervention.

The age distribution of the two groups was very similar. Patients receiving Coriolus versicolor supplementation had an average age of 31.7 years (minimum age of 19, maximum age of 49 years). The control group had an average age of 33.4 years (minimum age of 19 and a maximum of 51 years).


Of the 39 patients who completed one year of follow-up, 18 took Coriolus supplementation, while the other 21 patients received no therapy (Control group). After 1 year 13 of the 18 patients in the Coriolus group showed normal cervical cytology (72.5%) while only 10 of the patients in the control group did (47.5%).

Of the 39 patients, 22 were positive for high risk HPV subtypes.10 of these patients were in the Coriolus group and 12 in the control group. After 1 year 9 of the 10 in the Coriolus group had reverted to HPV- status (90%) while only 1 of the 12 in the control group had (8.5%).

What do these results mean for HPV patients?

The results from this study are encouraging and provide insight into the effectiveness of Coriolus versicolor as a useful immunonutrition agent. Using Coriolus supplementation for one year resulted in 72.5% of recipients reverting to normal cytology compares with only 47.5% of the control group. Encouragingly, 90% of the Coriolus recipients reverted to a HPV- status compared with only 8.5% in the control group.

While the study sample size is limited in number, the results strongly suggest that using Coriolus versicolor as a food supplementation agent offers doctors a useful nutritional tool when treating HPV (LSIL) patients over the age of 35 or those HPV (LSIL) patients with compromised immune systems.

It is also likely that Coriolus versicolor could be beneficial in HSIL patients who have undergone surgery but who experience recurrent lesions caused by persistent HPV viral infection; the eradication or “control” of the viral infection is key to both LSIL and HSIL patient care.

According to Dr Silva Couto, one of the study authors “At present, we believe that the optimal supplementation period may actually be as short as six months. Further testing is required to determine the best way to reduce the time period from the one year period used in this study.”. A shorter period of treatment would aid compliance as well as reducing the already minimal overall cost of therapy.

Why Coriolus versicolor?

As already stated, the mushroom Coriolus versicolor has been used in traditional Asian medicine for a long time. It is now known that Coriolus contains high quantities of Beta-glucans that act to stimulate the immune system. Studies have shown that Coriolus can double the number of natural killer cells after only 8-weeks of treatment.1,2 The benefits of treatment with the fungus has also been tested in patients with chronic fatigue syndrome. Coriolus versicolor (strain CV-OH1) is grown aseptically on sterile, edible grain, harvested and then produced as a tablet following good manufacturing practice according to pharmaceutical guidelines. It is free from pesticide, heavy metals and contaminants.

1. Jean A. Monro, Chronic Fatigue Immune Dysfunction Syndrome. J Integrative Medicine 2004;8:101-108

2. Jean A. Monro Treatment of Cancer with Mushroom Products. Arch Env Health 2003;58:533-537

Source: Medical News Today

Adjuvant PSK immunotherapy in patients with carcinoma of the nasopharynx.

A controlled study using adjuvant PSK immunotherapy in patients with nasopharyngeal carcinoma was initiated with the aim of improving survival by enhancing the host immune system against tumour cells. A total of 38 patients were randomly selected, all of whom had previously received radiotherapy with or without chemotherapy. Eight patients in the PSK immunotherapy group (n = 21) developed local recurrence, three of whom later died due to distant metastasis. In the control group (n = 17) three patients developed local recurrence while six patients developed distant metastasis. All of these six patients later died due to disease progression. It seems that PSK exerts its antitumour effect systemically; the risk of distant metastasis occurring is decreased, but it is apparently ineffective in improving local disease control. The estimated median survival time of the PSK-treated group compared with the control was significantly increased (35 months versus 25 months, P = 0.043). The 5-year survival rate was also significantly better in the PSK immunotherapy group (28% versus 15%, P = 0.043). It is concluded that PSK deserves careful consideration as an important immunotherapeutic agent in the management of nasopharyngeal carcinoma.