ScienceDaily (Sep. 26, 2009) — Huachansu, a Chinese medicine that comes from the dried venom secreted by the skin glands of toads, has tolerable toxicity levels, even at doses eight times those normally administered, and may slow disease progression in some cancer patients, say researchers from The University of Texas M. D. Anderson Cancer Center.

The results from the Phase I clinical study, a collaborative research project between M. D. Anderson and Fudan University Cancer Hospital in Shanghai, are reported in the online Early View feature of the journal Cancer. The study marks the first time a formal clinical trial has examined the relationship between huachansu dose and toxicity, although the drug is common in China and approved by the Chinese Food and Drug Administration.

Huachansu is widely used to treat patients with liver, lung, colon and pancreatic cancer at oncology clinics in China. Chinese clinical trials conducted since the 1970s have demonstrated the anti-cancer properties of huachansu, citing total response rates of 10 percent and 16 percent observed in patients with advanced hepatocellular carcinoma and lung cancer, respectively1,2.

“Studying traditional Chinese medicine such as huachansu is new to American research institutions, which have been skeptical and slow to adopt these complementary treatments. However, it is important to understand its potential role in treating cancer,” says Lorenzo Cohen, Ph.D., one of the paper’s authors and director of the Integrative Medicine Program at M. D. Anderson. “We wanted to apply a Western medicine-based approach to explore the role of the toad venom compound in cancer patients and test if it is possible to deliver a more potent dose without raising toxicities or side effects.”

The clinical trial was conducted at the Fudan University Cancer Hospital while M. D. Anderson provided training and ongoing consultation. The institutions collaboratively designed the trial that was approved by both institutional review boards. M. D. Anderson and Fudan University Cancer Hospital signed a sister institution agreement in 2003, creating a framework for research, educational and clinical collaboration.

The typical dose of huachansu used in China is approximately 15 milliliters of drug per meter squared of body mass (mL/m2). In the study, 15 patients with stage III or IV hepatocellular (liver) carcinoma, nonsmall cell lung cancer or pancreatic cancer received one of five dose levels ranging from 10 mL/ m2 up to 90 mL/m2 from January 2005 through July 2006. The treatment was repeated daily for 14 days followed by seven days off (one cycle). After two cycles, most patients received other treatments. Quality control methods were put in place to ensure huachansu of a uniform and consistent lot.

While the dose was up to eight times higher than conventional doses used in China, researchers observed only low toxicities or side effects. Eleven (73 percent) patients had no toxicities greater than the lowest grade measured. Importantly, no significant cardiac toxicity was observed and no significant changes in cancer-related symptoms occurred. Of the 15 patients who completed the treatment, six hepatocellular carcinoma patients (40 percent) had stable disease for a median of six months. One patient had a 20 percent reduction in tumor mass that lasted for more than 11 months.

“Even though we saw no complete or partial response (reduction of disease by 30 percent or more) it is encouraging that the cancer did not progress in a large set of the hepatocellular carcinoma patients,” says Zhiqiang Meng, principal investigator on the trial and an associate professor and deputy chair of the Department of Integrative Oncology at Fudan University Cancer Hospital, “Previous observations from studies conducted in China have shown that huachansu can inhibit tumor cell growth and improve immunologic function3. These findings, coupled with that knowledge, demonstrate the need for further clinical trials of this promising agent.”

A Phase II clinical trial comparing the effects of huachansu combined with gemcitabine (Gemzar®) to gemcitabine and placebo for patients with advanced pancreatic cancer is under way at the Fudan University Cancer Hospital in collaboration with M. D. Anderson.

Both trials are part of the International Center of Traditional Chinese Medicine for Cancer funded by the National Cancer Institute. Anhui Jinchan Biochemistry Company, Ltd. provided the drug for this trial.

In addition to Cohen, other M. D. Anderson faculty contributing to this study include Peiying Yang, MD, the Integrative Medicine Program in the Department of Medical Oncology; David Z. Chang, MD, Department of Gastrointestinal Medical Oncology; Zongxing Liao, MD, Department of Radiation Oncology; and Razelle Kurzrock, MD, Department of Investigational Cancer Therapeutics. In addition to Meng, other Fudan University researchers contributing to this study include Yehua Shen, MD; Wenying Bei, MD; Ying Zhang, MD; Yongqian Ge, MD; and Luming Liu, MD, PhD. Formerly of M. D. Anderson, Robert A. Newman, MD, now of New Chapter Inc. and Bob Thornton, MD, now of Merck & Co, Inc. also contributed to this study.

—Heather S. Oliff, PhD

Maitake (Grifola frondosa) is an edible mushroom used in East Asian traditional medicine. Laboratory and animal studies suggest that polysaccharides extracted from maitake have immune modulating and antitumor properties. Many cancer patients use maitake extract to boost their immune function. However, well-designed trials evaluating clinical benefits in people with cancer have not been conducted. Before such trials can be conducted, the optimal dose of maitake must be determined. The purpose of this trial was to evaluate the safety, tolerability, and immunological effects of a range of doses of maitake extract on women with breast cancer.   

This phase I/II dose-escalating trial was conducted at Memorial Sloan-Kettering Cancer Center in New York City. The trial included 34 postmenopausal women who had completed treatment for breast cancer and were cancer-free. The women were enrolled sequentially into 1 of 5 dose cohorts and took 0.2, 1.0, 3.0, 6.0, or 10 mg/kg per day of oral maitake extract (taken in 2 divided doses) for 21 days. The extract was prepared by extracting fruit bodies of maitake mushrooms with hot water and alcohol. The extract was provided by Yuikiguni Maitake Corporation through the Tradeworks Group (Brattleboro, Vermont). The extract was formulated in liquid form and packaged by Gaia Herbs (Brevard, North Carolina).

The women completed an interview and physical examination at the beginning and end of the study. They were instructed to report any adverse side effects or new symptoms immediately. Blood samples were collected before the women started taking the maitake extract and again at 7, 14, and 21 days after starting the extract. The blood samples were analyzed for cell type, cell markers, and intracellular production of cytokines, including several interleukins (IL), interferon-gamma (INF-γ), and tumor necrosis factor alpha (TNF-α).

The 34 women ranged in age from 38 to 77 years, with a median age of 55 years. Two women withdrew from the study because of adverse side effects. One woman in the 1.0 mg/kg cohort experienced nausea and joint swelling, and 1 woman in the 10 mg/kg cohort had a mild allergic reaction. No serious side effects were reported by any of the women.

There was a statistically significant relationship (P < 0.005) between the dose of maitake and the immunological response for 25 of the 146 measured parameters, which represented an overall statistically significant association between maitake and immunological function (P < 0.0005). Increasing the dose of maitake increased some immunologic parameters and depressed others. The largest increases were seen in granulocyte (a type of white blood cell) response; IL-10 production from certain types of cells (CD14+ and CD3+); IL-2 production from certain types of cells (CD56+ CD3+); and TNF-α production from CD3+ cells. All of these parameters had the largest increase at an intermediate dose of maitake (5-7 mg/kg per day, based on dose-response curves). For many of the immunologic parameters, intermediate doses had greater effects than higher or lower doses.

In summarizing the results of this trial, the authors state that maitake extract is associated with significant changes in certain immunologic parameters in the blood, that maitake extract has a stimulatory effect on some parameters and a suppressive effect on other parameters, and that the “optimal” dose of maitake extract varies for different immunologic parameters. The finding that maitake extract also increases some immune-suppressing cytokines in the blood contradicts the public perception that maitake boosts the immune system. In this study, maitake extract was well-tolerated, and no dose-limiting toxicity was observed. It is unclear if the tested extract is a marketed, and therefore available, extract.

The clinical significance of these immunological changes is unknown, particularly in the setting of cancer prevention and cancer treatment. Since maitake’s effects on immune function are complex, it should be viewed as an immune modulator rather than an immune enhancer.

Reference:

Deng G, Lin H, Seidman A, et al. A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: immunological effects. J Cancer Res Clin Oncol. 2009 Sep;135(9): 1215-1221.