Japanese Journal of Clinical Oncology Advance Access originally published online on November 14, 2006
Japanese Journal of Clinical Oncology 2006 36(12):808-810; doi:10.1093/jjco/hyl108
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© 2006 Foundation for Promotion of Cancer Research
An Alternative Medicine, Agaricus blazei, May Have Induced Severe Hepatic Dysfunction in Cancer Patients
1 Division of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, Chiba
2 Department of Medicine, Hamamatsu Oncology Center, Hamamatsu, Shizuoka
3 Division of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Hirofumi Mukai, Division of Oncology/Hematology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, Japan. E-mail: hrmukai{at}east.ncc.go.jp
Received May 8, 2006; accepted July 27, 2006
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Abstract |
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We report three cases of patients with advanced cancer who showed severe hepatic damage, and two of whom died of fulminant hepatitis. All the patients were taking Agaricus blazei (Himematsutake) extract, one of the most popular complementary and alternative medicines among Japanese cancer patients. In one patient, liver functions recovered gradually after she stopped taking the Agaricus blazei, but she restarted taking it, which resulted in deterioration of the liver function again. The other patients who were admitted for severe liver damage had started taking the Agaricus blazei several days before admission. Although several other factors cannot be completely ruled out as the causes of liver damage, a strong causal relationship between the Agaricus blazei extract and liver damage was suggested and, at least, taking the Agaricus blazei extract made the clinical decision-making process much more complicated. Doctors who are aware of their patients taking the extract may accept it probably because they believe there is no harm in a complementary and alternative medicine. When unexpected liver damage is documented, however, doctors should consider the use of the Agaricus blazei extract as one of its causal factors. It is necessary to evaluate many modes of complementary and alternative medicines, including the Agaricus blazei extract, in rigorous, scientifically designed and peer-reviewed clinical trials.
Key Words: alternative medicine • Agaricus blazei • fulminant hepatitis
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INTRODUCTION |
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Complementary and alternative medicine (CAM) is defined as a medical intervention which is not taught widely at medical schools or is not generally available in hospitals (1). The use of CAM has become common among many cancer patients worldwide. A summary of 26 surveys conducted across 13 counties estimated the prevalence of the use of CAM at 31.4% of all cancer patients, ranging from 7 to 64% (2), and this market may be growing as fast as 30% annually in the USA (3).
Despite the modest gains achieved in cancer treatment with multimodality therapies in the last decade, the majority of cancer patients with advanced-stage die of refractory and disseminated disease. Therefore, cancer patients who do not improve or feel beneficial effects from ordinary medicine expect CAM to cure their disease, prolong life, alleviate symptoms, improve their quality of life and boost their immune system. They value CAM for its medicinal potential. Another reason for using CAM is that they are believed not to have severe toxicities and may have the potential to control adverse effects caused by chemotherapy.
The great majority of patients taking CAM probably do so in conjunction with standard cancer therapies and usually do not stop using ordinary medicine that physicians recommend. A concern is that these adjunctive practices might pose risks to patients. There are theoretical reasons for thinking that some vitamin or herbal medicine might biochemically interfere with chemotherapy or radiation treatments, adversely alter treatment compliance, or cause side effects such as hepatic injury (4–6).
Agaricus blazei (Himematsutake) is a mushroom-derived compound and is widely used among cancer patients in Japan. As is the case with other CAM compounds, no scientific evidence supports their safety or efficacy. We report here three cancer patients who took Agaricus blazei extract and showed severe hepatic dysfunction.
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CASE REPORT |
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Case 1
A 66-year-old woman with stage IIIC ovarian cancer was scheduled to receive post-operative combination chemotherapy with cisplatin and cyclophosphamide (CDDP+CPA) for six cycles. She had no particular past history including allergic reaction. Following the first cycle of chemotherapy, she had a fever of 39.6°C and elevation of transaminases (peak AST:392, ALT:292, T-bil:4.7) was documented (Fig. 1). Liver function was recovered thereafter. The second cycle of the chemotherapy was given on the due date and the same events occurred. She was diagnosed as having chemotherapy-induced hepatitis and the following doses and all other medications were withheld. However, the transaminase levels continued to fluctuate significantly for unknown reasons. Her disease recurred 8 months after the operation but continuing elevated transaminase prevented the sufficient use of systemic chemotherapy. She disclosed to her doctor at her terminal stage that she had been taking Agaricus blazei extract at the time of chemotherapy following her friend's recommendation. She was advised to withhold its use and her liver function returned to normal.
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Case 2
A 58-year-old woman was admitted to our hospital because of general fatigue. She had had a right mastectomy for her stage IIIA breast cancer 9 months previously and had received six cycles of cyclophosphamide+doxorubicin+5FU (CPA+ADR+5FU:CAF regimen) for adjuvant chemotherapy. The interval duration from the cessation of chemotherapy to this admission was 3 months.
Upon admission, AST, ALT, t-bilirubin and prothrombin time were 231 IU/l, 1226 IU/l, 6.6 mg/dl and 18 s respectively, and no causative factors such as drugs, viruses or alcohol intake were documented. Recurrence of breast cancer was not demonstrated. She had started to take Agaricus blazei extract a few days before her admission. The liver damage and her level of consciousness gradually deteriorated on the day following admission. She subsequently died with severe liver damage 7 days after her admission.
Case 3
A 48-year-old woman with metastatic breast cancer in the bone started to receive chemotherapy with doxorubicin and cyclophosphamide (ADR+CPA). Before the chemotherapy, serological tests revealed that she was a chronic carrier of hepatitis B virus (HBV) (positive for HBs antigen and anti-HBe antibody and negative for HBe antigen) and the serum transaminase levels were normal. After three cycles of the chemotherapy, she complained of appetite loss (National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2, grade 2), nausea and vomiting (NCI CTC version 2, grade 2). She was admitted to the hospital because of hepatic dysfunction (AST, 5265; ALT, 7365; T-bil, 5.3). A test for HBV-DNA with a polymerase chain reaction assay indicated viral replication. She said she had taken Agaricus blazei extract and no other drugs for several days before admission. She was diagnosed as having acute hepatitis and it developed rapidly. She was transferred to another hospital for plasma exchange therapy but died of fulminant hepatitis 6 days after.
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DISCUSSION |
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We report three cases that showed severe hepatic dysfunction during the course of cancer treatment or follow-up, two of whom died of fulminant hepatitis. All of them had episodes of oral intake of Agaricus blazei extract, but no other conventional or CAM regimens were used. It is indeed difficult to clearly identify the Agaricus blazei extract as the cause of the liver dysfunction, because other causative factors such as cancer chemotherapy and hepatitis virus cannot be completely ruled out. However, it should be noted that concurrent use of the Agaricus blazei extract made the differential diagnosis process rather complicated.
In case 1, the liver function recovered gradually after the patient stopped taking the Agaricus blazei extract, but when she restarted taking the extract, it deteriorated again. This time course suggests a strong causal relationship between the Agaricus blazei extract and the liver dysfunction.
The patient in case 2 told her doctor at the time of admission that she had started taking the Agaricus blazei extract several days before admission. No other causative factors were documented. This episode strongly suggests that the Agaricus blazei extract induced the fatal liver dysfunction.
The third patient was a chronic carrier of HBV. It has been well documented that cancer chemotherapy such as CHOP (cyclophosphamide+doxorubicin+vincristine+prednisolone) activates hepatitis B virus replication in patients in the chronic carrier status (7,8), especially as a result of high doses of steroid. However, reactivation of hepatitis by AC regimen at the standard dose has not yet been reported. Although the ultimate reason of the severe hepatic damage could not be known, it cannot be ruled out that the use of the Agaricus blazei extract might have some adverse influence on the nonreplicable phase of HBV infection.
Some CAM agents have been reported to be toxic and may interact with other medications (9,10). It has also been reported that some herbs photosensitize the skin and cause severe reactions when used in combination with radiation therapy (9).
In general, patients are reluctant to report their use of CAM to their doctors (11). A recent study suggests that physicians are unaware of 80–90% of all CAM use if the patients do not directly inform the physician about such practices (12). Physicians should take the initiative and have discussions about the usage of CAM with their patients. A close doctor–patient relationship including good communication is one way to limit the use of ineffective or toxic CAM agents, saving the patients from abandonment or disinformation. Especially when unexpected liver damage is documented, doctors should consider the use of the Agaricus blazei extract as one of the causal factors for the phenomenon.
In the available studies concerning practitioners of CAM, it was found that 60% of the providers of such treatments were medical physicians. The remaining 40% were chiropractors, naturopaths, homeopaths, or nutritionists, some of whom were trained in institutions with marginal academic standards (13). Physicians who provide CAM should acknowledge that many CAM lack sufficient safety and efficacy data.
CAM today represents a medical and social phenomenon that cannot be ignored and requires the need for proper research. The broad dissemination of untested therapies is an unacceptable practice. CAM, including the Agaricus blazei extract should be evaluated in rigorous, scientifically designed clinical trials (14).
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References |
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