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 DOI: 10.1177/1534735413510022

2014 13: 161 originally published online 25 November 2013Integr Cancer TherBing Yan, Xianze Meng, Jun Shi, Zhifeng Qin, Pinkang Wei and Lixing Lao

Spore Induced CA72-4 Elevation in Gastrointestinal Cancer: A Five-Case ReportGanoderma lucidum  

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Article

Introduction

Due to the limitations of conventional cancer treatment, large numbers of cancer patients turn to complementary and alternative medicine,1,2 most commonly traditional Chinese medicine (TCM).3 Ganoderma lucidum (Figure 1A), also known as Lingzhi or Reishi, is a species of basidiomycete. It was recorded in the oldest Chinese materia medica, Classical Pharmacopeia of the Heavenly Husbandman (206 BC-8 AD) and has been used in China for more than 2000 years.4 It is well known as the “mushroom of immor-tality,” widely used in China and many Asian countries to promote longevity, maintain vitality, and treat multiple dis-eases, including gastrointestinal cancer.5-8 Since the 1980s, its anticancer properties, such as cytotoxicity, immunomod-ulation, and the ability to suppress angiogenesis and induce apoptosis, have been investigated.7-10

As an over-the-counter supplement, this fungus has been commercially processed into many products,11,12 one of which, Ganoderma lucidum spore (GLS; Figure 1B), is becoming increasingly popular among cancer patients in Asian countries.13,14 Clinical observations of GLS have shown that it may be effective in treating gastrointestinal cancer with few adverse effects15: animal studies demon-strate that long-term toxicity in rats only occurs at dosages higher than 5.40 g/kg, which corresponds to 60 times of the

clinical human dosage.16 However, the clinical safety evalu-ation of this remedy is far from sufficient.

In the current report, we describe 5 cases of gastrointes-tinal cancer. Each of these patients presented with a surge of the serum tumor marker CA72-4 after taking GLS; how-ever, no disease progression was observed. Although the underlying mechanism of this reaction is obscure, our cases indicate that additional studies are urgently needed since a consistent rise of CA72-4 is generally thought to be indica-tive of disease progression17,18 and physicians would con-ventionally shift the treatment for these patients.

All GLS administered to these patients was processed using standard quality controls with a composition ratio of 1:4 of Ganoderma lucidum sporophore and broken GLS. The high performance liquid chromatograms (HPLC) of the samples are shown in Figure 2.

510022 ICTXXX10.1177/1534735413510022Integrative Cancer TherapiesYan et alresearch-article2013

1Second Military Medical University, Shanghai, China2University of Maryland, Baltimore, MD, USA

Corresponding Author:Zhifeng Qin, Department of Traditional Chinese Medicine, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Email: yanbing3741@gmail.com

Ganoderma lucidum Spore Induced CA72-4 Elevation in Gastrointestinal Cancer: A Five-Case Report

Bing Yan, PhD1, Xianze Meng, PhD1, Jun Shi, PhD1, Zhifeng Qin, MD1, Pinkang Wei, MD1, and Lixing Lao, MD2

AbstractGanoderma lucidum spore (GLS), an over-the-counter herbal supplement, is widely used by cancer patients in China. Although preclinical studies have shown it to be safe, complete safety data on GLS is still lacking. In this article, we report 5 cases of gastrointestinal cancer that were treated with GLS plus multiple strategies between 2010 and 2011. These patients presented with increased levels of the serum tumor marker CA72-4, one of the most valuable markers for monitoring therapeutic response in patients receiving gastrointestinal cancer treatment, after oral ingestion of GLS twice a day for 1 or 2 months. Interestingly, CA72-4 rapidly returned to normal levels when the patients discontinued the supplement and no change in clinical symptoms accompanied the CA72-4 surge. Taking into consideration that the underlying mechanism of this reaction is obscure, we suggest that additional studies are urgently needed and GLS be used with caution in cancer patients.

Keywordsgastrointestinal cancer, CA72-4, alternative medicine, Ganoderma lucidum spore, case report

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162 Integrative Cancer Therapies 13(2)

Case Reports

Case 1

A 64-year-old man was diagnosed in 2010 with gastric ade-nocarcinoma (Table 1). After a distal subtotal gastrectomy, he underwent 5 one-month cycles of chemotherapy. He responded to treatment for only 4 months before carcinoem-bryonic antigen (CEA) and CA72-4 levels began to rise (ref-erence values = 0-5 µg/mL and 0-8.2 U/mL, respectively). Along with a new chemotherapy regimen, he began taking 6 capsules (1.8 g) of GLS a day as a dietary supplement. One month later, when the CA72-4 had surged to 126.30 U/mL and the CEA was still rising, we suggested that he stop the GLS and try an alternative herbal medicine, Hua Chansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or Bufo melanostictus, which was commonly used to treat gastrointestinal cancer.19 After 2 cycles of treatment, the CA72-4 values fell into the normal range. He began taking GLS again; a month later, the CA72-4 had sharply risen to 435.78 U/mL, so the supple-ment was stopped. When he came to our department for follow-up 1 month later, CA72-4 levels had returned to nor-mal and the CEA level had decreased (Figure 3A). An enhanced computed tomography scan of the abdomen 6 months after the last CA72-4 surge showed no progression of the disease. During the treatment, his liver function indexes all remained within the normal range.

Case 2

A 77-year-old man was diagnosed in 2010 with gastric ade-nocarcinoma (Table 1). After a total gastrectomy and

splenectomy, he underwent 5 cycles of chemotherapy. The response was good; only his CEA value was greater than the reference level, and it trended toward the normal range. He then presented in our department to obtain the alternative treatment β-elemene,20,21 which was a naturally occurring compound isolated from the TCM herb Curcumae Radix22 and began using 1.8 g of GLS a day as a dietary supplement (β-elemene was not stopped in the subsequent treatment). His CA72-4 level immediately surged to 99.23 U/mL; it fell back into the normal range a month after the GLS was stopped (Figure 3B). He visited our department for 8 more months, during which we detected no progression of the disease. During the treatment, his liver function indexes remained normal.

Case 3

A 61-year-old woman was diagnosed in 2009 with gastric adenocarcinoma (Table 1). After a radical proximal gastrec-tomy and gallbladder resection, she responded to chemother-apy for only 4 months before her CEA and CA72-4 levels began to rise. We recommended an alternative herbal medi-cine, Xiao Aiping, a Chinese medicine that comes from Glaucescent Fissistigma Root, which was frequently used for gastrointestinal cancer in China.23 After 3 cycles of treatment, the CEA value had increased to 54.51 µg/L, but the CA72-4 had declined to normal. She then took GLS as dietary supple-ment along with the Xiao Aiping, which was continuously applied in the subsequent treatment. A month later, the CA72-4 had surged to 99.92 U/mL and the CEA to 60.83 µg/L. Dramatically, both the CA72-4 and CEA dropped sharply by the next month without any change in treatment. The GLS was then withdrawn, and the CEA and CA72-4 both rapidly fell into the normal range (Figure 3C). Ten months later, when she visited our department for follow-up, we detected no progression in her disease. During the treatment, her liver function indexes remained within the normal range.

Case 4

A 56-year-old man was diagnosed in 2008 with anastomotic gastric adenocarcinoma (Table 1). Initially, he used Hua Chansu19 as a treatment. Serum tumor markers were moni-tored every month; after 24 one-month cycles of treatment, CEA and CA72-4 were normal, as was liver function. He then took GLS as a dietary supplement accompanied with Hua Chansu. The CA72-4 titer increased sharply to 562.30 U/mL by the 1-month follow up; it decreased rapidly to 27.65 U/mL 2 months after withdrawal of the GLS. Throughout this period, the CEA only showed small changes (Figure 3D). The patient was followed by our department for 8t more months, during which we detected no progression of his disease. During treatment, his liver function remained normal.

Figure 1. Fruiting body of Ganoderma lucidum (A) and Ganoderma lucidum spore (B).

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Yan et al 163

Case 5

A 59-year-old woman was diagnosed in 2010 with colorec-tal cancer (Table 1). After radical surgery, she responded to

chemotherapy for 6 months before her CEA levels began to rise. She stopped chemotherapy and began Xiao Aiping23 plus 1.8 g of GLS a day (Xiao Aiping was not ceased in the subsequent treatment). Her CA72-4 had surged to 287.10

Figure 2. HPLC-DAD of the sample. Samples were randomly tested 10 times, and the absorbance was at 280 nm.

Figure 3. Multiples of the measured values of CA72-4 and CEA compared to their respective reference values at various treatment stages.

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164 Integrative Cancer Therapies 13(2)

U/mL 1 month later, and her CEA had risen slightly. She stopped the GLS. Her CA72-4 immediately returned to nor-mal, and her CEA also became normal after 2 months (Figure 3E). Our department followed her for 9 months, during which an enhanced abdominal computed tomogra-phy scan detected no progression of the disease. During treatment, her liver function remained normal.

Discussion

With herbal therapies becoming increasingly popular among cancer patients, it is important for physicians to rec-ognize the effects of such therapy in their patients since the majority of these agents are commonly not subjected to pre-market toxicity examination to test their safety or effi-cacy.24,25 As shown in Figure 2, all 5 gastrointestinal cancer patients experienced a surge of the serum tumor marker CA72-4 after taking GLS. Except in Case 3, the supplement was withdrawn immediately when their CA72-4 levels surged, after which their levels decreased sharply to refer-ence levels. Interestingly, in Case 3, the only patient who kept using GLS after her CA72-4 level peaked, CA72-4 also sharply decreased after an initial month of increase. Additionally, although 1 patient experienced a surge in CEA along with the rise in CA72-4, the patients showed no significant change in clinical symptoms, and in follow-up we found no progression in disease. These data demonstrate that GLS, alone or combined with other agents, may induce the elevation of CA72-4. However, this elevation may not correlate with disease progression.

Our cases do highlight concerns regarding the safety of GLS. GLS is an herbal remedy containing multiple constit-uents, not all of which have been identified. However, the preparation is known to contain major bioactive compo-nents such as ergosterol, triterpenoids, unsaturated fatty acids, and polysaccharides,12,26-28 all of which are generally

believed to be safe. Furthermore, in animal studies the LD50 of GLS has been shown to be more than 10.0 g/kg with no mutagenic or teratogenic action, which suggests that GLS is probably safe.29

CA72-4 is one of the most valuable markers for monitor-ing response to treatment in gastric cancer patients30-34 and that an increase in level of this tumor marker may invari-ably heralds disease progression; however, the phenomenon of tumor marker surge during treatment is registered in some special conditions, which should catch our attention. Previous studies report that cytotoxic drugs can induce a surge in serum tumor markers. For example, Sørbye and Dahl report a transient CEA increase at the start of oxalipla-tin combination therapy for metastatic colorectal cancer; the CEA levels peaked between 13 and 56 days, and the median rise from baseline was 263%.35 Loprinzi et al found a CEA surge in 14 of 29 responding metastatic breast cancer patients treated with dibromodulcitol, doxorubicin, vincris-tine, tamoxifen, and fluoxymesterone (DAVTH) or DAVTH alternating with cyclophosphamide, methotrexate, 5-fluoro-uracil, and prednisone (CMFP); the mean rise was 243% of pretreatment CEA levels.36 This phenomenon was com-monly interpreted as the result of more powerful chemo-therapy agents inducing greater tumor cell lysis. In our Case 3, the only patient who continued GLS for a long period, CA72-4 surged rapidly when GLS was initiated and then sharply decreased, as did CEA, without any change in treat-ment, thus mirroring the aforementioned studies. Taking into consideration that studies demonstrate that the GLS extract possesses direct cytotoxic effects on cancer cells through multiple mechanisms such as apoptosis, cell cycle arrest, and enhanced cell-mediated immune response,37-40 there is a possibility that the surge of CA72-4 might be due to GLS-produced tumor cell lysis. However, evidence to support this hypothesis is lacking as no other clinical symp-tom improvements accompanied the CA72-4 surge.

Table 1. Clinical Pathology of the 5 Patients.

Patient Gender Age Disease Stagea

CA72-4 Values Associated With GLS (U/mL)

Beforeb Duringc Afterd

1 Male 64 GA T3N1M0 65.07 435.78 5.522 Male 77 GA T4bN1M0 7.75 99.23 1.843 Female 61 GA T4bN0M0 8.09 99.92 8.814 Male 56 GA —e 12.88 562.30 27.655 Female 59 CA T2N0M0 3.18 287.10 7.76

Abbreviations: GLS, Ganoderma lucidum spore; GA: gastric adenocarcinoma; CA: colorectal cancer; AJCC, American Joint Committee on Cancer.aThe stages follow AJCC gastric cancer guidelines (2010, 7th version).bThe last CA72-4 value detected before the first use of GLS.cPeak value of CA72-4 during GLS treatment.dThe CA72-4 value of Patient 4 was obtained 2 months after GLS was discontinued; the other patients’ values were taken 1 month after discontinuation of the supplement.eAnastomotic gastric adenocarcinoma, not applicable to the AJCC staging system.

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To date, the production mechanism of CA72-4 in cancer cells is not well illustrated. An additional possibility for the surge of CA72-4 in our cases is that GLS may directly or indirectly modulate CA72-4 production without a corre-sponding promotion of either tumor progression or antitu-mor effects. In such a scenario, tumor cells may not be growing while GLS is effectively promoting CA72-4 pro-duction. However, we cannot draw clear conclusions based on the current data.

The history of mushroom use for medicinal purposes began with TCM more than 5000 years ago, and on most occasions, these agents are categorized as “generally regarded as safe,”8 but a long history of use, traditions, faith, popularity, and anecdotes cannot always be taken as evidence for the safety of these agents.41 Although our cases may indicate that the usage of GLS in gastrointestinal can-cer patients be harmless, it cannot be taken as an evidence for its free application in patients. Rigorous evidence for its safety or efficacy can only be obtained from randomized controlled trials in the future.

Conclusion

Our cases suggest that the safety of GLS in cancer patients should be further studied. GLS should be used with cau-tion, and patients should be carefully monitored and followed-up.

Acknowledgments

We thank Dr Lyn Lowry of the Center for Integrative Medicine, University of Maryland School of Medicine, for her editorial support.

Authors’ Note

Bing Yan and Xianze Meng contributed equally. Other authors contributed to language translation, editing, and scientific advice.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors(s) received no financial support for the research, authorship, and/or publication of this article.

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