14651858cd007731pub3 230504 212505

Cochrane Database of Systematic Reviews
Ganoderma lucidum
(Reishi mushroom) for cancer treatment (Review)
Jin X, Ruiz Beguerie J, Sze DMY, Chan GCF
Jin X, Ruiz Beguerie J, Sze DMY, Chan GCF.

#Ganoderma lucidum (Reishi mushroom) for cancer treatment.
Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD007731.
DOI: 10.1002/14651858.CD007731.pub3.
www.cochranelibrary.com
Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review)

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 1.1. Comparison 1 Treatment response, Outcome 1 WHO criteria. . . . . . . . . . . . . . . 22
Analysis 2.1. Comparison 2 Host immune functions, Outcome 1 Leukocyte. . . . . . . . . . . . . . . 22
Analysis 2.2. Comparison 2 Host immune functions, Outcome 2 NK activity. . . . . . . . . . . . . . . 23
Analysis 2.3. Comparison 2 Host immune functions, Outcome 3 CD3. . . . . . . . . . . . . . . . . 23
Analysis 2.6. Comparison 2 Host immune functions, Outcome 6 CD4/CD8. . . . . . . . . . . . . . . 26
Analysis 3.1. Comparison 3 Quality of life, Outcome 1 Karnofsky score (dichotomous)). . . . . . . . . . . 27
Analysis 3.2. Comparison 3 Quality of life, Outcome 2 Karnofsky score. . . . . . . . . . . . . . . . . 27
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 37
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) i

[Intervention Review]
Ganoderma lucidum (Reishi mushroom) for cancer treatment
Xingzhong Jin1 , Julieta Ruiz Beguerie2 , Daniel Man-yeun Sze3 , Godfrey CF Chan4
1
Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. 2 Dermatology Department, Austral University
Hospital, Buenos Aires, Argentina. 3 School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia. 4 Department
of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
Contact address: Xingzhong Jin, Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, Tasmania,
7000, Australia. xingzhong.Jin@utas.edu.au.
Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 4, 2016.
Review content assessed as up-to-date: 4 February 2016.
Citation: Jin X, Ruiz Beguerie J, Sze DMY, Chan GCF. Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane
Database of Systematic Reviews 2016, Issue 4. Art. No.: CD007731. DOI: 10.1002/14651858.CD007731.pub3.
ABSTRACT
Background
Ganoderma lucidum is a natural medicine that is widely used and recommended by Asian physicians and naturopaths for its supporting
effects on immune system. Laboratory research and a handful of preclinical trials have suggested that G. lucidum carries promising
anticancer and immunomodulatory properties. The popularity of taking G. lucidum as an alternative medicine has been increasing in
cancer patients. However, there is no systematic review that has been conducted to evaluate the actual benefits of G. lucidum in cancer
treatment.
Objectives
To evaluate the clinical effects of G. lucidum on long-term survival, tumour response, host immune functions and quality of life in
cancer patients, as well as adverse events associated with its use.
Search methods
We searched an extensive set of databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EM-
BASE, NIH, AMED, CBM, CNKI, CMCC and VIP Information/Chinese Scientific Journals Database was searched for randomised
controlled trials (RCTs) in October 2011. Other strategies used were scanning the references of articles retrieved, handsearching of the
International Journal of Medicinal Mushrooms and contact with herbal medicine experts and manufacturers of G. lucidum. For this
update we updated the searches in February 2016.
Selection criteria
To be eligible for being included in this review, studies had to be RCTs comparing the efficacy of G. lucidum medications to active or
placebo control in patients with cancer that had been diagnosed by pathology. All types and stages of cancer were eligible for inclusion.
Trials were not restricted on the basis of language.
Data collection and analysis
Five RCTs met the inclusion criteria and were included in this review. Two independent review authors assessed the methodological
quality of individual trials. Common primary outcomes were tumour response evaluated according to the World Health Organization
(WHO) criteria, immune function parameters such as natural killer (NK)-cell activity and T-lymphocyte co-receptor subsets, and
quality of life measured by the Karnofsky scale score. No trial had recorded long-term survival rates. Associated adverse events were
Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 1
reported in one study. A meta-analysis was performed to pool available data from the primary trials. Results were gauged using relative
risks (RR) and standard mean differences (SMD) for dichotomous and continuous data respectively, with a 95% confidence interval
(CI).
Main results
The methodological quality of primary studies was generally unsatisfying and the results were reported inadequately in many aspects.
Additional information was not available from primary trialists. The meta-analysis results showed that patients who had been given G.
lucidum alongside with chemo/radiotherapy were more likely to respond positively compared to chemo/radiotherapy alone (RR 1.50;
95% CI 0.90 to 2.51, P = 0.02). G. lucidum treatment alone did not demonstrate the same regression rate as that seen in combined
therapy. The results for host immune function indicators suggested that G. lucidum simultaneously increases the percentage of CD3,
CD4 and CD8 by 3.91% (95% CI 1.92% to 5.90%, P < 0.01), 3.05% (95% CI 1.00% to 5.11%, P < 0.01) and 2.02% (95% CI
0.21% to 3.84%, P = 0.03), respectively. In addition, leukocyte, NK-cell activity and CD4/CD8 ratio were marginally elevated. Four
studies showed that patients in the G. lucidum group had relatively improved quality of life in comparison to controls. One study
recorded minimal side effects, including nausea and insomnia. No significant haematological or hepatological toxicity was reported.
Authors’ conclusions
Our review did not find sufficient evidence to justify the use of G. lucidum as a first-line treatment for cancer. It remains uncertain
whether G. lucidum helps prolong long-term cancer survival. However, G. lucidum could be administered as an alternative adjunct to
conventional treatment in consideration of its potential of enhancing tumour response and stimulating host immunity. G. lucidum
was generally well tolerated by most participants with only a scattered number of minor adverse events. No major toxicity was observed
across the studies. Although there were few reports of harmful effect of G. lucidum, the use of its extract should be judicious, especially
after thorough consideration of cost-benefit and patient preference. Future studies should put emphasis on the improvement in
methodological quality and further clinical research on the effect of G. lucidum on cancer long-term survival are needed. An update to
this review will be performed every two years.
PLAIN LANGUAGE SUMMARY

G. lucidum (Reishi mushroom) for cancer treatment
There have been an increasing number of patients diagnosed with cancer each year. Certain malignancies have been a major cause
of death in some populations. People who have been diagnosed with cancer want to do everything they can to combat the disease,
manage its symptoms and cope with the side effects of radio/chemotherapy. Many turn to complementary and alternative medicine.
G. lucidum extract is a medication that has been widely used by traditional Chinese medicine (TCM) practitioners for this regard. It is
usually recommended as an immune system support supplement in cancer treatment. Latest laboratory research and preclinical trials of
G. lucidum have shown promising results of its antitumour activity. However, clinical evidence of its efficacy is sparse and a systematic
review is in need to provide collective information for health-care consumers.
Our review identified and subsequently included five relevant randomised controlled trials. A total of 373 subjects were analysed. A
meta-analysis was performed to pool available data from individual trials. Our results found that patients with G. lucidum extract in
their anticancer regimen were 1.27 times more likely to respond to chemotherapy or radiotherapy than those without. However, the
data failed to demonstrate significant effect on tumour shrinkage when it was used alone. In addition, G. lucidum could stimulate
host immune functions by considerably increasing CD3, CD4 and CD8 lymphocyte percentages. Nevertheless, natural killer (NK)-
cell activity, which has been suggested to be an indicator of self-defence against tumour cell, was marginally elevated. Patients in the
G. lucidum group were found to have a relatively better quality of life after treatment than those in the control group. A few cases of
minor side effect associated with G. lucidum treatment including nausea and insomnia were reported.
There are limitations of the results from this systematic review. First, most included studies were small and there were concerns on the
methodological quality of individual trials. Second, all participants in the individual trials were recruited from the Chinese population.
Together, the robustness and applicability of the results were largely affected.

BACKGROUND The polysaccharides from G. lucidum are believed to trigger an
indirect antitumour mechanism in which the host immune system
is altered to target the tumour cells. The active polysaccharides are
Description of the condition largely in the form of beta-glucans. It has been shown that beta-
glucans have the ability to induce both innate and adaptive im-
In the year 2000, malignant tumours were responsible for 12% of mune responses. The targeted immune cells include macrophages,
56 million deaths worldwide from all causes. Around 5.3 million neutrophils, monocytes, natural killer (NK) cells and dendritic
men and 4.7 million women developed a malignant tumour and cells. The branched chains of beta-glucans act on complement
together 6.2 million people died from their disease. According to receptor type 3 (CR-3) triggering a series of molecular pathways
the World Cancer Report by World Health Organization (WHO), such as NF-κB, mitogen-activated protein kinase (MAPK) and
cancer rates could further increase by 50% to 15 million new cases protein kinase C (PKC), which in turn, activate the host immune
by 2020 (Steward 2003). Chemotherapy and radiotherapy are two response for immune cell proliferations (Hong 2004). Beta-glu-
routinely used adjuvant treatments for cancer patients in conven- cans also act on dectin-1 receptor and toll-like receptor 2 (TLR-
tional medicine. A variety of adverse events are associated with 2) (Brown 2006; Gantner 2003). The resultant actions are en-
these two treatments, such as myelosuppression, gastrointestinal hanced maturation of dendritic cells as well as increased opsonic
discomfort and disorder, alopecia, fatigue, and even cardiac, respi- and non-opsonic phagocytosis. Subsequently, cytokine produc-
ratory and neural toxicity. These side effects have affected patients’ tion and splenic NK-cell cytotoxicity are increased (Chan 2007).
long-term compliance to medication and have lowered their qual- All of these immune reinforcements are believed to have a contri-
ity of life (QoL) (ONS 2005). As a result, numerous oncology bution to the antitumour properties of G. lucidum (Sliva 2003).
studies have been initiated in order to find an alternative cancer In addition, G. lucidum is the only known source of a particular
medication over the past few decades. Ganoderma lucidum (G. lu- group of triterpenes, also known as ganoderic acids, which have
cidum) is one such substance that has been widely studied in tra- been found to have direct cancer cell cytotoxicity on a wide variety
ditional Chinese medicine (TCM) (Boh 2007). of cancer cell lines, such as murine Lewis lung carcinoma (LLC)
and Meth-A, and many of them have been suggested to counter
angiogenesis and metastasis (Min 2000).
Description of the intervention
G. lucidum [Latin] (also known as Reishi in Japan, Ling-zhi in
Why it is important to do this review
China, Ling chih, and Ling chi mushroom in other countries) is a
type of mushroom that grows on plum trees in Asia. It is popular Prompted by the promising anticancer potential established by
among consumers in Japan and is widely used by Asian physicians laboratory studies, a few randomised controlled trials (RCTs) have
and herbalists. This medicinal mushroom has been used in Asia been conducted to evaluate the clinical effectiveness of G. lucidum.
for thousands of years to increase energy, stimulate the immune However, the majority of clinical trials are conducted in Asia and
system, and promote health and longevity (Chang 1999). In the published in Asian databases. Full-text publications are usually
US, G. lucidum is included in the American Herbal Pharmacopoeia not available in English. To date, there is no systematic review
and is most often recommended for its immune-supporting ef- that investigates the clinical usefulness of G. lucidum for cancer
fects (Upton 2000). In Poland and other countries outside Asia, treatment. Since the prevalence of G. lucidum use in cancer patients
G. lucidum is used as a daily food supplement that adapts itself has been increasing, the clinical usefulness of G. lucidum for cancer
to correct imbalances in the body (Jong 1992). Influenced by an treatment needs to be scrutinised. Therefore, a systematic review
increasing number of studies into G. lucidum, modern uses of G. based on existing RCTs is needed to provide up-to-date knowledge
lucidum include treatment for coronary heart disease, arterioscle- of G. lucidum in clinical practice, and to provide direction for
rosis, hepatitis, arthritis, nephritis, bronchitis, hypertension, can- future clinical trials in this field.
cer and gastric ulcers (Boh 2007).
OBJECTIVES
How the intervention might work
To investigate the overall effectiveness of G. lucidum for the treat-
A systematic laboratory research elucidates that the anticancer and
ment of various cancers and its impact on long-term cancer sur-
immunomodulatory properties of G. lucidum are largely contained
vival rates.
in its diverse chemical constituents, whereas polysaccharides and
triterpenes are two groups of prominent bioactive components To evaluate the immunomodulatory effects of G. lucidum and its
(Chan 2005; Lee 1998). impact on the QoL of cancer patients.

METHODS The WHO criteria for tumour response were developed and pub-
lished in the early 1980s (WHO 1979, Miller 1981). It has been
adopted as the standard method for evaluating tumour response
Criteria for considering studies for this review to treatment. The evaluation is dependent on measurement of
tumour size. Change of tumour size after treatment is estimated
from bi-dimensional measurement (the product of the longest di-
Types of studies ameter and its longest perpendicular diameter for each tumour).
There are four categories of response: complete response, partial
Eligible study designs were RCTs regardless of language and pub- response, stable disease and progressive disease.
lished status (published, pending, ongoing or unpublished). Clus-
ter RCTs and randomised cross-over studies were also eligible. For
randomised cross-over studies, only first phase data were included
in the review. Other study designs were excluded. 2.2 Response Evaluation Criteria in Solid Tumour (RECIST)
RECIST is a validated evaluation criteria of cancer drugs for clin-
Types of participants ical trials, published in February 2000 by an international collab-
oration including the European Organization for Research and
Adult patients who were diagnosed with malignant tumour, re-
Treatment of Cancer (EORTC), National Cancer Institute (NCI)
gardless of origin, tumour stage, age and gender. The diagnosis
of the US and the National Cancer Institute of Canada Clini-
must have been confirmed by biopsy.
cal Trials Group (Patrick 2000). RECIST is an approach based
only on measurements in one dimension from new imaging tech-
Types of interventions niques, such as computer tomography (CT) and magnetic res-
onance imaging (MRI). As with the WHO criteria, tumour re-
Intervention of interest was medication extracted from the plant
sponses for RECIST are divided into four categories: complete
G. lucidum, irrespective of preparations (raw plant, decoction,
response, partial response, stable disease and progressive disease*.
capsule, tablet, tincture, extract, injection) dosage and regimen.
* A Korean study (Park 2003) comparing the WHO criteria and
The medication could be derived from any part of G. lucidum
the RECIST guidelines has concluded that two criteria guidelines
(mycelium, stem, root, leave, spore).
are comparable in evaluating response in solid tumours.
As a comparison, eligible control included no intervention/
placebo, active conventional therapies (surgery, chemotherapy and
radiotherapy) and other complementary and alternative medicines
Secondary outcomes
(CAM). All medications apart from active conventional therapies
were regarded as CAM.
Eligible intervention combinations are listed in Table 1.
3. Host immune functions
Peripheral leukocyte count, phagocyte indexˆ or phagocyte activ-
Types of outcome measures
ity*, T-cell and B-cell subset lymphocytes flow cytometry, NK-
Outcomes of interest were measured at the baseline of a trial, at cell activity, and tumour necrosis factor (TNF-α) level.
the end of interventions and at the end of follow-up. ˆ The average number of bacteria ingested by each phagocyte in
an individual’s blood after a mixture of the blood serum, bacteria
and phagocytes has been incubated.
Primary outcomes
* The percentage of neutrophils that phagocytose.
1. Overall survival rate

4. Quality of life (QoL)
One-year, three-year and five-year survival resulting from all causes
QoL was evaluated with any validated instrument, such as QOLS
of death.
original Flanagan version (Flanagan 1982), Karnofsky score or
original evaluation instrument used in the primary studies.
2. Treatment response
5. Adverse events
Incidence of all major and minor adverse events such as digestive
2.1 WHO response criteria upsets, skin rashes and hepatotoxicity.

Search methods for identification of studies from identified studies. Details of individual studies were stored as
paper documents with corresponding reference IDs in EndNote.
A literature search was performed to identify relevant RCTs from
January 1980 to October 2011, regardless of published status
(published, pending, ongoing or unpublished) and language of Selection of studies
publication. We updated the searches in February 2016 (CEN-
Two review authors (XJ and JRB) independently engaged in the
TRAL (Issue 1 2016)(Appendix 1), MEDLINE (Oct 2011 to Jan
selection of studies and the assessment of eligibility for inclusion
week 4 2016)(Appendix 2), EMBASE (Oct 2011 to 2016 week
with any disagreement to be resolved by discussion. By screening
5)(Appendix 3)).
titles, abstracts and keywords, information of identified studies
was entered in an I/O form (Appendix 4). Full texts were further
Electronic searches assessed if the collected information suggested that a primary study
Following electronic databases were searched: was eligible for this review. When information contained in a study
• the Cochrane Central Register of Controlled Trials was not sufficient to make a judgement on its eligibility, attempt
(CENTRAL), on The Cochrane Library, was made to contact the corresponding study authors and to obtain
• MEDLINE, further details of the original study. A third review author (DS)
• EMBASE, helped translate studies in different languages into English before
• National Institute of Health (NIH), abstract and full text was examined.
• Allied and Complementary Medicine Database (AMED),
• Evidence-Based Medicine Review (EBMR), featuring Inclusion Criteria
Cochrane DSR, ACP Journal Club, DARE, CCTR, CLCMR
1. RCTs, including cluster RCTs and randomised cross-over
and CLHTA,
trials.
• Chinese Biomedical Literature Database (CBM),
2. Human studies.
• China National Knowledge Infrastructure (CNKI),
3. Participants with a confirmed diagnosis of cancer.
• Chinese Medical Current Content (CMCC),
4. G. lucidum involved in at least one observational arm.
• VIP Information/Chinese Scientific Journals Database.
5. Investigation of at least one outcome as mentioned
We also searched clinical trials registries in order to identify ongo- previously.
ing studies:
• International Standard Randomised Controlled Trial
Number Register (ISRCTN), Exclusion Criteria
• Clinical Trials.gov (clinicaltrials.gov), 1. Any study designs other than RCTs.
• National Center for Complementary and Alternative 2. Animal studies and in vitro studies.
Medicine (nccam.nih.gov/clinicaltrials/alltrials.htm), 3. Participants with no cancer diagnosis.
• Chinese Clinical Trial Register (www.chictr.org), 4. G. lucidum not involved as an intervention.
• WHO International Clinical Trial Registration Platform 5. No outcome of interest observed.
Search Portal (www.who.int/trialsearch),
• Australian and New Zealand Clinical Trial Registry (
www.anzctr.org.au/). Data extraction and management
We used a standard extraction form (Appendix 5) to collect data
from each included trial and categorise into the following items:
Searching other resources 1. General information: publishing status, language, authors,
We made an attempt to identify further published and unpub- article title, journal title and year, volume, issue, page and
lished trials by viewing the list of references from the individual funding source.
studies that were retrieved from the electronic searches. We did 2. Participants: diagnostic criteria, total number and number
a handsearch of theInternational Journal of Medicinal Mushrooms. in comparison groups, baseline characteristics, age, gender,
Experts in this field and manufacturers of G. lucidum were also inclusion criteria, exclusion criteria and study setting.
contacted in order to locate further relevant articles. 3. Intervention: type of preparation, dose, regimen, co-
intervention, withdrawals, loss to follow-up.
4. Outcome: primary outcomes, secondary outcomes and
Data collection and analysis other outcomes at the end of treatment and/or the end of follow-
up. The adverse events recorded will also be extracted.
All identified studies were recorded in EndNote 2. Two review 5. Data analysis: study data in detail, statistical methods for
authors (XJ and JRB) were assigned to collect and extract data data analysis.

Assessment of risk of bias in included studies such asymmetry (Harbord 2005). P < 0.10 was deemed to have
Corresponding authors of primary studies were contacted in order considerable small-study effects.
to obtain further methodological details of the original trials. Po-
tential bias in trials was assessed using a ’Risk of bias’ assessment Data synthesis
form (Appendix 6). Individual primary study was appraised inde-
Where appropriate, differences in outcomes comparing treatment
pendently by two review authors (XJ and JRB) according to the
and control groups were combined across studies using generic
criteria (Appendix 7) that are described in Cochrane Handbook for
inverse-variance methods for meta-analysis. All data analyses were
Systematic Reviews of Interventions (Higgins 2011). Based on the
performed on RevMan 5. Summary estimates were presented in
criteria, studies were summarised into three categories: low risk of
forest plots.
bias, moderate risk of bias and high risk of bias. Discrepancy was
Fixed-effect model was used. If there was presence of heterogeneity
settled by further discussion and a final judgement was made from
among studies, we compared results between fixed-effect model
the consensus between two review authors.
and random-effects model.
Survival rates, treatment response and adverse events were consid-
Measures of treatment effect ered to be dichotomous data. For treatment response regardless
of which criteria were used, responders were defined as patients
Treatment effect of interest was observed at the baseline of a trial,
who achieved complete response or partial response according to
at the end of intervention of interest and at the end of follow-up.
the criteria, while other patients who had a result of stable disease
or progressive disease were considered as non-responders (Chinn
Unit of analysis issues 2000).
Host immune function indicators and scores of QoL were treated
We made efforts to obtain individual patient data (IPD) or any
as continuous data when data obtained was sufficient and appro-
missing aggregated data by contacting corresponding authors of
priate. In cases where data for the same outcome were presented as
included studies. Where data were sufficient, a time-to-event anal-
dichotomous data in some studies and as continuous data in other
ysis was conducted.
studies, we contacted the corresponding authors for any missing
data. When the authors were not able to be contacted, we con-
Dealing with missing data verted the dichotomous data into continuous data by using the
method introduced in Section 9.4.6 of the Cochrane Handbook for
We tried to obtain missing data from corresponding trialists. The
Systematic Review of Interventions (Higgins 2011).
impact of missing data was analysed via comparison between re-
Relative risk (RR) and its 95% CI were used for estimating the
sults including missing data and results excluding missing data.
overall effects of dichotomous data. Weighted mean difference
(WMD) and its 95% CI were used for continuous data if an
outcome had been measured using the same scale, or else standard
Assessment of heterogeneity
mean difference (SMD) would be used instead.
Heterogeneity was assessed by inspecting the forest plots. Confi-
dence intervals (CI) of studies overlapping with each other and the
summary effect implied no or insignificant heterogeneity present. Subgroup analysis and investigation of heterogeneity
In addition, heterogeneity was tested by both Chi2 test and I2 test. Subgroup analyses were planned to carry out in terms of the fol-
A result of Chi2 > 25% and P < 0.10 was defined as evidence of lowing aspects:
significant heterogeneity across studies. I2 test was used to esti- 1. Different dosage regimens of G. lucidum treatment.
mate the extent of variability across studies that was due to hetero- 2. Different origins of tumour.
geneity. A result higher than 30% would represent moderate het- 3. Different stages of cancer.
erogeneity and higher than 50% would represent substantial het- 4. Whether or not combined with active conventional
erogeneity (Higgins 2003). Possible sources of heterogeneity were treatments or (and) other complementary medications in
explored by subsequent subgroup analyses and sensitivity analyses. addition to G. lucidum treatment.
5. Different parts of G. lucidum used in the trials (e.g. spore
versus mycelium).
Assessment of reporting biases
Funnel plots of treatment effect against its standard error were
used to explore publication bias and ’small-study effects’, depend- Sensitivity analysis
ing on the number of primary studies included in this systematic Sensitivity analyses were prespecified to explore the influence of
review. Asymmetry in funnel plots implied possible small-study the following factors:
effects. A modified ’Egger’ regression test was conducted to detect

1. Repeating data analysis excluding unpublished studies (if cancer, one (Leng 2003) in post-surgical rectal cancer and one (He
there is any). 1997) in various cancers with the same TCM symptomatology.
2. Compare analysis including missing data against analysis
excluding missing data.
3. Compare analysis excluding studies with high risk of bias
Excluded studies
against the original meta-analysis.
Excluded studies and reasons for exclusion were listed in
Characteristics of excluded studies.
RESULTS
Risk of bias in included studies
Description of studies
Allocation
Results of the search
All included studies made a statement in their reports that the al-
Our search yielded a total of 257 studies from the electronic location of study subjects was randomised, but none of them pro-
databases. After screening off repetitive and clearly irrelevant stud- vided explicit description. In one study (Zhang 2000), the subjects
ies, 35 studies remained eligible for abstract and full-text assess- were allocated according to enrolment order and it was unclear
ment. Six reviews, 10 non-randomised trials, two case reports whether efforts had been made to achieve allocation concealment.
and one irrelevant trial were further excluded. Two RCTs (Huang Review authors therefore judged that there might be considerable
2001; Wang 2005) were excluded because no outcome of interest selection bias in this study. One study (He 1997) included very
was observed in the study. Seven RCTs (Jing 2007; Liang 2002; limited information with regard to random sequence generation
Ma 2003; Mo 1999; Pan 2007; Zhang 1999; Zhuang 2009) were and a very high risk of selection bias was suggested by the marked
further excluded due to the use of herbal mixture instead of pure difference in size between two arms, 100 in observation versus 60
G. lucidum and one study (Song 2006) was also excluded because in control.
another species G. capense in the family was used. Another RCT
(Kuang 2007) was excluded after scrutiny over the text because
it appeared to have apparent reporting errors. It reported that 56
patients were randomly allocated into two equal groups, however Blinding
the total number of patients was 39 in the experiment and 17 in In two studies (Gao 2003b; Zhang 2000), a placebo of same ap-
the control when tumour responses were reported. The remaining pearance and taste had been specifically invented and used in or-
five RCTs were included in this systematic review. One ongoing der to blind both patients and doctors to study design. Other in-
study (Matthew 2010) was identified on the clinical trial registers. cluded studies were open trials where blinding had not been done
The status of the study was complete yet unpublished. Contact or attempted in an inappropriate manner. Two studies (He 1997;
with the corresponding trialist to retrieve trial data was attempted; Yan 1998), in which outcomes potentially influenced by subjective
however, the trialist refused to disclose any data from the trial. judgement of patients or clinicians were measured, such as QoL,
From the 2016 updated searches we retrieved an additional 74 were particularly subject to a high risk of detection bias. Whereas
references. However, no additional studies were identified for in- other studies in which objective testing (e.g. blood count, NK-
clusion. cell activity and T-lymphocyte subsets) was the only measure, the
results of these studies were unlikely to be affected by the absence
of blinding.
Included studies
Five RCTs were included in this systematic review. Four of them
were retrieved from Chinese databases and full-texts were reported
Incomplete outcome data
in Chinese. Only one RCT (Gao 2003b) was reported in English
and was able to be identified on EMBASE or MEDLINE. All In the He 1997 study, 160 cancer patients were recruited into
trials evaluated the effectiveness of commercial preparations of G. the trial but only 10 patients were included in the haematological
lucidum. Except for one study (He 1997) in which 160 patients analysis. No explanation was found in the text for the incomplete
were enrolled, most individual studies were small trials with a outcome data. In the Gao 2003b study, eight subjects (five in
sample size less than 100. Three studies (Gao 2003b; Yan 1998; the treatment group and three in the control group) were lost to
Zhang 2000) evaluated the effects of G. lucidum in advanced lung follow-up and excluded from the final data analysis.

Selective reporting treatment when G. lucidum was incorporated into a cancer treat-
We tried to contact the authors of all included studies in order ment regimen with chemo/radiotherapy. In contrast, in the Yan
to obtain trial protocols and IPD. Unfortunately none of the au- 1998 study and the Zhang 2000 study patients who received G.
thors could be reached to provide the information. Reporting bias lucidum treatment in combination with conventional chemother-
could therefore only be assessed on the basis of available published apy generally responded more positively than those in the standard
study reports. In the He 1997 study, investigations in lymphocyte, treatment group.
platelet and immunoglobulins were proposed in the Methods sec-
tion but data were omitted in the Results section. 3. Host immune functions
For studies in which only the means of values at the baseline and
Other potential sources of bias endpoint were reported, the mean difference (MD) and standard
deviation comparing before and after treatment were computed
In one study (He 1997), there was a significant imbalance between
according to the following formula:
the observation group and the control group in terms of number
MD(C) = MD(A) - MD(B);
of subjects. We could not obtain further details from the study
SD(C) = SQRT(SD(B)2 + SD(A)2 - 2*R*SD(B)*SD(A))
author, and there was no explanation for this in the report. This
MD, mean difference; SD, standard deviation; SQRT, square root;
raised review authors’ concerns on pseudo-randomisation or other
R was defined as a value of 0.5 in this review.
potential bias.
A, endpoint measures; B, baseline measures; C, value change in
measures.
Effects of interventions
3.1 Leukocyte
Change in leukocyte count (× 109 /L) after treatment was measured
1. Survival rate in only one study (Yan 1998), which showed that G. lucidum
treatment had the property of attenuating leukocytic depletion
No included study had recorded survival data; hence data analysis resulted from the cytotoxicity of chemotherapy (MD 1.52; 95%
in this regard was unavailable in this review. CI 0.59 to 2.45; P = 0.12) (Analysis 2.1).
2. Treatment response 3.2 NK-cell activity

Three included studies (Gao 2003b; Yan 1998; Zhang 2000) had Two studies (Gao 2003b; Zhang 2000) had measured the effect
measured the short-term response of lung cancer to G. lucidum of G. lucidum on boosting NK-cell activity. The results from these
treatment according to the WHO criteria (1979). As prespecified two studies showed completely opposite directions in effect. While
in the protocol of this review, complete response or partial re- the results of the Gao 2003b study favoured the use of G. lucidum
sponse were categorised as positive responses while other responses, and showed an increase in NK-cell activity after its use, the Zhang
including stable disease and progressive disease, were defined as 2000 study did not support the same and even indicated a slightly
a negative response. The data extracted from the primary stud- negative impact. As a result, our meta-analysis yielded a statistically
ies were pooled and presented in a forest plot (Analysis 1.1). In insignificant overall value (SMD 0.45; 95% CI -1.60 to 2.50; P =
the Gao 2003b study, no cancer patients in either G. lucidum or 0.67) with a substantial degree of heterogeneity (Chi2 = 17.78; P
placebo arm yielded a positive outcome, therefore the study was < 0.01; I2 = 94%) (Analysis 2.2).
not able to contribute to the analysis. The RR pooled from the
other two studies suggested that tumour shrinkage was more likely
when patients were on G. lucidum, however the result was statis- 3.3 T-cell subsets
tically insignificant (RR 1.50; 95% CI 0.90 to 2.51; P = 0.12). All included studies but one (He 1997) had measured complete
This result should be taken with caution because G. lucidum may T-lymphocyte subset counts. From the pooled results, it showed a
not have a significant antitumour effect when it is used as a solitary general improvement of immunological status in cancer patients
treatment. This was particularly demonstrated by the equally zero who had taken G. lucidum treatment (Analysis 2.3; Analysis 2.4;
case of positive response in both arms in the Gao 2003b study, Analysis 2.5; Analysis 2.6). Overall, the value of CD3 was in-
where neither G. lucidum nor placebo was used in company with creased by an average of 3.91% (95% CI 1.92% to 5.90%; P <
any conventional therapy. Although patients in the G. lucidum 0.01), CD4 by 3.05% (95% CI 1.00% to 5.11%; P < 0.01), as
group had a relatively lower PD rate (51.4%) after treatment, com- well as CD8 by 2.02% (95% CI 0.21% to 3.84%; P = 0.03). There
pared to that of those who received placebo (67.7%), the author was only a marginal improvement in terms of the CD4/CD8 ratio
speculated that tumours were more likely to respond to cancer with an overall increase of 0.12 (95% CI 0.01 to 0.23; P = 0.03).

Interestingly, all immune parameters in the Zhang 2000 study from the other three included studies (Gao 2003b; Leng 2003;
were decreased in the G. lucidum group, which were in opposition Yan 1998).
to results of the other three studies. A number of factors might
have contributed to the conflict of results, including small sam-
ple size, poor methodological quality (especially due to high risk
in randomisation failure) and statistical randomness. The study
also contributed to the significantly high I2 value observed in the
analysis. Exclusion of the study from the analysis could resolve DISCUSSION
the high heterogeneity test values, however there was no strong
rationale for such exclusion, particularly in consideration of lim- The objective of this systematic review was to evaluate the efficacy
ited number of studies in our analysis. Again, we believe that small and safety of G. lucidum in cancer treatment using evidence from
sample size and poor methodology are the major contributors to RCTs. The intention of meta-analysis is to pool available data
the significant heterogeneity among the studies. from individual trials to produce an overall summary measure
of effects, including long-term survival rates, tumour response,
immune response and QoL.
4. Quality of life (Karnofsky score)
The impact on QoL by the incorporation of G. lucidum treat-
ment was evaluated in four studies by comparing the Karnofsky
scores (Gao 2003b; He 1997; Yan 1998; Zhang 2000). One study Summary of main results
(Zhang 2000) reported the mean changes in score values after A total of five RCTs with 373 subjects were included in this review
treatment and the other three (Gao 2003b; He 1997; Yan 1998) and subsequent meta-analysis. Our results suggested that incor-
presented the results in a format of dichotomous data. Therefore, poration of G. lucidum treatment could potentially improve tu-
we combined the data separately according to the type of data mour response of lung cancer to conventional therapy. In other
(Analysis 3.1; Analysis 3.2). Qualitatively, the use of G. lucidum words, G. lucidum could have a synergetic potential with chemo/
in cancer patients had a positive impact on QoL, as more subjects radiotherapy to obtain an increase in CR/PR rates in patients with
had achieved an increase in Karnofsky score after intervention in lung cancer. However, there is no current evidence that has shown
the G. lucidum group than the control group (RR 2.51; 95% CI that the increased tumour response would translate into improved
1.86 to 3.40; P < 0.01). Quantitatively, the results from the Zhang long-term survivals. In addition, our review does not support the
2000 also favoured the use of G. lucidum. Average Karnofsky score use of G. lucidum as a stand-alone treatment for cancer treatment
was decreased in both groups after intervention, but the value was as its antitumour effect was found to be almost negligible when it
less affected in the patients receiving G. lucidum treatment com- was used alone and was evaluated by the WHO criteria of tumour
pared to placebo, resulting in a relatively positive MD favouring response (WHO 1979).
G. lucidum treatment despite the difference being statistically in- Our findings also showed that G. lucidum could be capable of en-
significant (MD 12.70; 95% CI -4.72 to 30.12; P = 0.15). hancing immunity in cancer patients by stimulating T-lympho-
cyte proliferation, suggesting that G. lucidum could be a promising
adjunct to counter the unwanted but common immunosuppres-
5. Adverse events
sive effect of many chemotherapeutic drugs. Overall, CD3, CD4
One study (Gao 2003b) reported three episodes of toxicity in pa- and CD8 percentages were improved or less depleted by 3.91%,
tients receiving G. lucidum treatment. Two experienced nausea and 3.05% and 2.02%, respectively, after G. lucidum treatment for one
one had insomnia. No patients developed hepatitis or abnormal to three months, compared to standard treatments. However, NK-
liver function tests. No haematological or biochemical toxicity was cell activity, which had been postulated by a number of studies
recorded in all included studies. in this field to be an important mechanism of G. lucidum’s anti-
tumour effect (Gao 2003a; Gao 2005b; Brittenden 1996; Zheng
2011), was found to be little changed in our review and the results
6. Subgroup analyses and sensitivity analyses were inconclusive.
Because of limited number of trials and insufficient IPD from pri- QoL was relatively improved in cancer patients with G. lucidum
mary studies, prespecified subgroup analyses could not be carried treatment than without. Overall Karnofsky score was relatively
out. A sensitivity analysis comparing high-risk studies and low- increased qualitatively and quantitatively in patients after G. lu-
risk studies was performed when investigating lymphocyte subset cidum treatment. Only one study recorded minor adverse events
results. As stated previously, the inadequate subject randomising associated with the use of G. lucidum. Side effects included minor
method and the lack of allocation concealment in the Zhang 2000 GI tract upset (nausea) and sleep disturbance (insomnia). No ma-
study might have largely contributed to its discrepancy in results jor haematological or hepatological toxicity was observed.

Overall completeness and applicability of fortunately, the obvious imbalance of subject numbers between
evidence groups, along with its poor study design and reporting standards,
had compromised its robustness of evidence. All studies clearly
Antitumour effect and immunity enhancement are the two major
reported loss to follow-up and incomplete data.
properties of G. lucidum as suggested by preclinical studies. Our
The small sample size and unclear risk of random sequence gen-
review focused on the assessment of survival rate, tumour response
eration were the two greatest disadvantages in regard to the qual-
and immune function indicators, while QoL and adverse events
ity of the evidence in this review. The Zhang 2000 study was the
were also investigated. However, up to the date of this review,
smallest study and had a high risk in random sequence generation
no RCT has investigated whether G. lucidum treatment produces
due to the use of alternate assignment approach and the absence
benefits on survivals in the long term. Among all included studies,
of allocation concealing strategy. The impact of these two fac-
the RCT conducted by Gao 2003b was so far the most compre-
tors were demonstrated when T-lymphocyte subgroup data were
hensive trial in which all the outcomes of interest except survival
pooled. The study yielded an opposite direction of effect against
rates had been investigated. We were able to assess the short-term
three other studies and largely contributed to the significant het-
tumour response evaluated by the WHO criteria (WHO 1979).
erogeneity among studies.
The results favoured the incorporation of G. lucidum into con-
ventional treatment but more studies are needed to confirm this.
The effects of G. lucidum on leukocyte and NK-cell activity were
inconclusive and controversial in our review due to the insufficient
Potential biases in the review process
number of studies reporting these outcomes. Given the available
data at the time of this review, we were able to conclude a positive We have performed a thorough literature search for both published
effect of G. lucidum on T lymphocyte proliferation, as well as on and unpublished studies from an extensive set of databases. The
QoL of cancer patients. literature search has not been restrained by language limitations.
The improved tumour response is only applicable to lung cancer All available trials have been included in the systematic review. We
patients as it is the only type of cancer that was investigated in have investigated all the important end points including benefits
terms of short-term treatment response. Whether this effect would and harms instead of solely looking at a particular measurement.
occur in different subtypes of lung cancer is unknown due to We have been able to provide some clarification on the clinical
insufficient IPD. In addition, the positive outcomes of treatment usefulness of G. lucidum in cancer treatment.
response are only applicable when lung cancer patients are given However, our review also has limitations. First, data retrieved from
G. lucidum regimen along with traditional standard treatment. T- the primary studies were rather sparse. We were not able to perform
lymphocyte proliferation was generally increased by G. lucidum a meta-analysis on all the important outcomes prespecified in the
regardless of the type of cancer. Other possible co-founding factors, protocol, for example, long-term survival rates. Second, there was a
for example age, could not be compared because of the scarcity great divergence in the methodological quality of included studies,
of IPD. Coincidentally, all five primary studies recruited research with some being of low risk of bias and the other having high risk of
subjects from the Chinese population. Thus, it is possible that bias. Inclusion of the high-risk studies into our meta-analysis could
there could be some variations in effects when the results in this have led to biased or misleading results. The sensitivity analyses
review are applied to other demographical groups. performed in our review have also shown methodological quality
could have been a key factor that had influenced the opposing
results across studies. Third, despite our effort to be free of regional
limitations, the studies identified and included in this review all
Quality of the evidence evaluate effects on subjects from the Chinese population. Such
Overall, the methodological quality of the included studies was unintentional bias may have resulted in restriction and uncertainty
unsatisfactory. Most trials failed to detail the process of random when it comes to application of the results from our review.
sequence generation and the strategy of allocation concealment Finally, we have not been able to perform all the subgroup analyses
clearly in the report. The randomisation process is critical to pre- that were predefined in the protocol due to small number of trials
vent allocation bias, but it is difficult to evaluate when the details in the subgroups. Thus we have not been able to differentiate the
of the process is not included in the report and we were unable effectiveness of G. lucidum in the treatment for different types
to contact the corresponding authors. Three out of five included and stages of cancer, making the results of our review relatively
studies were open trials, of which two were subject to high risk indefinite and somewhat over generalised.
of bias when a subjective score of QoL was measured. Among all
the studies, Gao 2003b was of the highest methodological qual-
ity while He 1997 was on the other end of the spectrum. Para-
doxically, the He 1997 study was the biggest clinical trial and the
Agreements and disagreements with other
only included study that had a sample size over 100 subjects. Un-
studies or reviews

This review is the first systematic review and meta-analysis to in- the published reports, have jeopardised the reliability and validity
vestigate the effectiveness of G. lucidum for cancer treatment. De- of the original trials. Future studies should make efforts to address
spite the fact that preclinical studies have established promising the following issues of trial design and reporting:
antitumour properties of G. lucidum extract, the results of this
meta-analysis do not conclusively confirm the findings from pre- 1. Full details of the enrolment sequence generation and
vious studies. The use of G. lucidum alone does not demonstrate subsequent strategy for allocation concealment should be
significant clinical benefits in achieving a better tumour response. included in the published reports.
Our review shows that G. lucidum can relatively improve immune
functions that are usually depressed by chemo/radiotherapy, which 2. True randomisation (e.g. shuffling envelopes or computer
is consistent with previous clinical trials and reviews. Past reviews random numbers) should be adopted instead of simple or
speculated that enhanced cytokine production and NK-cell ac- pseudo-randomisation (e.g. hospital record number).
tivity are factors that contribute to the anticancer property of G. 3. Clinicians, patients and assessors should be blinded (e.g.
lucidum, however, the results of this review show that the effect of use of a placebo) to prevent conscious or subconscious bias that
G. lucidum on NK-cell activity is negligible. may subsequently invalidate the results.
4. An intention-to-treat (ITT) analysis should be applied to all
future trials to avoid bias and false-positive results. Complete
AUTHORS’ CONCLUSIONS information and reasons for participants who are enrolled and
allocated to treatment groups but drop out of the assigned
Implications for practice groups, should be provided.
The five studies included in this review do not provide clear and 5. Standardisation of methods of data presentation and data
unbiased evidence to support the first-line use of G. lucidum in analysis. Reporting of results should be improved according to
treatment for cancer patients. There is lack of evidence to support standard guidelines (CONSORT 2010).
the point that the use of G. lucidum in advanced cancer therapy
In this review, we have been able to clarify the beneficial effect
improves long-term survival. We do not recommend administra-
from G. lucidum on tumour response, immune functions and QoL
tion of G. lucidum preparations as a single treatment to patients
assessment. The findings are relatively general and vague. Future
with advanced cancer. However, the results of this review suggest
clinical trials should explore the clinical potential of G. lucidum in
that a better response may be expected when a G. lucidum prepara-
the following aspects:
tion is incorporated as an adjuvant in conventional chemo/radio-
therapy regimens. Regimens that incorporate G. lucidum are 1.25
times more likely to yield a better tumour response than those do 1. The effect of G. lucidum on one particular type of cancer
not. Also, G. lucidum preparations can be administered in order should be further explored so as to differentiate the effectiveness
to counter the immunosuppressive effect of chemo/radiotherapy, of G. lucidum across different types of malignancy.
especially in terms of T-lymphocyte depletion. Similar to other 2. The staging of cancer should be standardised and well
natural remedies, G. lucidum is well-tolerated by cancer patients documented in future trials so that the responsiveness of
leading to better QoL and a relatively improved Karnofsky score. different stages of cancer to G. lucidum treatment can be
No severe toxicity has been observed according to current evi- compared in future reviews.
dence. In short, current evidence does not support routine use of
G. lucidum in all cancer patients. The decision of whether to use a 3. Long-term survival is an important end-point assessment
G. lucidum preparation in an anticancer regimen should be made and should be investigated in any clinical trials of patients with
after careful consideration of cost-benefit potential and patients’ cancer. It is of utmost importance to decide the clinical
preferences. Given the results of this review and from a cultural usefulness of an agent in cancer treatment.
perspective, it could beneficial to add G. lucidum to the regimen 4. Data from demographic groups other than the Chinese
for patients who have a Chinese background. population are needed to explore the clinical applicability of G.
lucidum in the future.
Implications for research
Currently, the evidence of using G. lucidum for cancer is sparse
and the methodological quality of the trials is poor. As a result,
we have only been able to draw a few definite conclusions from
ACKNOWLEDGEMENTS
the evidence. The lack of standardisation in several aspects among
included trials, for example uniformed preparation and adminis- We thank Markus Horneber and Chris Williams for editorial ad-
tration of G. lucidum, and failure to include key information in vice; Claudia Lodaza-Can, Nerida Klupp and Kathie Godfrey for

their peer review comments and Gail Quinn for coordinating title
registration and review submission.
This project was supported by the National Institute for Health
Research, via Cochrane Infrastructure funding to the Cochrane
Gynaecological, Neuro-oncology and Orphan Cancer Group. The
views and opinions expressed therein are those of the authors and
do not necessarily reflect those of the Systematic Reviews Pro-
gramme, NIHR, NHS or the Department of Health.
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Gao 2003b
Methods Randomised, double-blind, placebo-controlled, multicentre clinical trial
Participants 68 patients with histologically confirmed advanced stage (stage III or IV) lung cancer
Interventions Ganopoly vs. placebo
Outcomes Treatment response (WHO criteria), QoL (Karnofsky score), immune functions (lym-
phocyte transformation, NK activity, CD subsets), adverse reactions
Notes -
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Insufficient information regarding the ran-
bias) domisation process was provided in the
text. Size and characteristics of groups are
comparable
Allocation concealment (selection bias) Unclear risk No explicit information of allocation con-
cealment
Blinding (performance bias and detection Low risk Patients and doctors were blinded, a
bias) placebo of same shape, colour and size was
All outcomes used
Incomplete outcome data (attrition bias) Low risk 8 patients were lost to follow-up (5 in treat-
All outcomes ment group and 3 in placebo group)
Selective reporting (reporting bias) Low risk Protocol is unavailable from the authors.
Based on the publication itself, selective re-
porting is unlikely
Other bias Low risk The study seems to be free of other sources
of bias

He 1997
Methods RCT
Participants 160 various cancer patients (100 intervention, 60 control)
Interventions Lingzhi spore powder capsule + chemo/radiotherapy vs. chemo/radiotherapy
Outcomes QoL (Karnofsky score), blood count (WBC, Hb)
Notes Data from only 10 patients are obtained for blood count
Risk of bias
Random sequence generation (selection High risk Very limited information about sequence generation. Significant
bias) difference in size between groups suggests randomisation prob-
ably is not done
Allocation concealment (selection bias) High risk No information regarding allocation concealment
Blinding (performance bias and detection High risk An open trial in which QoL is an outcome of observation
bias)
All outcomes
Incomplete outcome data (attrition bias) High risk Only 10 patients were compared for blood count, although no
All outcomes missing data in assessing QoL
Selective reporting (reporting bias) High risk Investigation in lymphocyte, platelet and immunoglobulins are
mentioned in the Methods but are missing in the Results
Other bias High risk Significant imbalance between the number of patients of inter-
vention group and that of control groups
Leng 2003
Methods RCT
Participants 60 patients after colon cancer surgery
Interventions Zhengqing Lingzhi liquid vs. routine therapy
Outcomes T-cell subgroups, clinical symptoms
Notes -
Risk of bias

Leng 2003 (Continued)
Random sequence generation (selection Unclear risk Randomisation process is not detailed in the publication
bias)
Allocation concealment (selection bias) Unclear risk No information of allocation concealment
Blinding (performance bias and detection Low risk An open trial, but no subjective outcome was investigated, hence
bias) review authors believe this will not introduce bias
All outcomes
Incomplete outcome data (attrition bias) Low risk No incomplete outcome data reported
All outcomes
Selective reporting (reporting bias) Low risk Protocol is unavailable. It is not common that T-cell subsets
are the only observation in a trial of cancer treatment, however
review authors do not believe this would introduce significant
bias in the meta-analysis
Other bias Low risk No other sources of bias is found
Yan 1998
Methods RCT
Participants 56 patients non-parvicellular lung cancer
Interventions Laojunxian Lingzhi oral liquid + chemotherapy vs. chemotherapy alone
Outcomes WHO criteria, Karnofsky score, haematological parameters, T-cell subgroups
Notes -
Risk of bias
Random sequence generation (selection Unclear risk Sequence generation process is not detailed, simple randomisa-
bias) tion may have been used and results in uneven sample size be-
tween arms
Allocation concealment (selection bias) Unclear risk No explicit information on allocation concealment
Blinding (performance bias and detection High risk No blinding was attempted, QoL is likely to be subject to bias
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk No incomplete outcome data
All outcomes

Yan 1998 (Continued)
Selective reporting (reporting bias) Low risk The study protocol is not available, no selective reporting is
found in the text
Other bias Low risk No other sources of bias is found in the text
Zhang 2000
Methods RCT
Participants 29 patients diagnosed as stage III or IV lung cancers
Interventions Lingzhi tablet vs. placebo
Outcomes Karnofsky score, TNF, sIL-2R, T-cell subgroups, NK activity, haematological parameters
Notes -
Risk of bias
Random sequence generation (selection High risk Sequence generated by enrolment order
bias)
Allocation concealment (selection bias) High risk No explicit information of allocation concealment. Given an in-
appropriate random sequence generation, review authors believe
it would introduce considerable selection bias
Blinding (performance bias and detection Low risk A placebo is specifically designed to achieve blinding
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Each arm has 2 subjects lost to follow-up
All outcomes
Selective reporting (reporting bias) Low risk The study protocol is not available, no selective reporting in the
text
Other bias Low risk No other sources of bias is found
Hb: haemoglobin; NK: natural killer; QoL: quality of life; RCT: randomised controlled trial; sIL-2R: soluble interleukin-2 receptor;
TNF: tumour necrosis factor; WBC: white blood cell; WHO: World Health Organization.

Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Chen 2006 Non-randomised
Gao 2003a Non-randomised, non-controlled, before-after study
Gao 2004 Review
Gao 2005a Non-randomised, non-controlled, before-after study
Gao 2005b Non-randomised, open-labelled trial
Gill 2008 Non-randomised trial
Huang 2001 No outcome of interest
Jia 2005 Non-randomised trial
Jing 2007 Intervention consists of multiple herbal ingredients
Kuang 2007 This study may be a fraud. 56 patients were allegedly randomised into 2 equal groups (each group should have 28
cases), however we found 39 cases in the experiment group and 17 cases in the control group. In spite of this, the
trialists still used 28 as a denominator in all the data analyses
Li 2000 Do not have outcomes of interest
Liang 2002 Intervention consists of multiple herbal ingredients
Ma 2003 Intervention consists of multiple herbal ingredients
Mahajna 2009 Review
Mo 1999 Intervention consists of multiple herbal ingredients
Niu 2002 Case report
Pan 2007 Intervention consists of multiple herbal ingredients
Qi 1999 Non-randomised trial
Simerpal 2008 Non-randomised trial
Sliva 2003 Review
Sliva 2006 Review
Song 2006 Use of G. capense instead of G. lucidum

(Continued)
Wang 1999 Non-randomised trial
Wang 2005 Does not have outcome of interest: it is a nursing study that observed side effects of chemotherapy (phlebitis and
irritation sign of bladder)
Xu 2000 Case report
Yuen 2005 Review
Zhang 1999 Intervention consists of multiple herbal ingredients
Zhou 2001 Non-randomised trial
Zhou 2005 Review
Zhuang 2009 Intervention consists of multiple herbal ingredients
Characteristics of ongoing studies [ordered by study ID]
Matthew 2010
Trial name or title A randomised, double-blind, placebo-controlled, parallel study of the clinical effects of Ganoderma lucidum
(Ling Zhi) in children with cancer
Methods Randomised, double-blind, placebo-controlled, parallel study
Participants Target sample size: 58
Interventions Lingzhi capsule
Outcomes Generic and cancer-specific paediatric QoL assessment; cellular immune functions; blood counts and bio-
chemistry for patient safety; infection-related morbidities; overall and event-free survival
Starting date September 2002
Contact information Matthew MK Shing, MBBS, FRCP, Department of Pediatrics, Prince of Wales Hospital, The Chinese Uni-
versity of Hong Kong
Notes Trialist was contacted, however, was not willing to disclose any data
QoL: quality of life

DATA AND ANALYSES
Comparison 1. Treatment response
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 WHO criteria 3 153 Risk Ratio (IV, Fixed, 95% CI) 1.50 [0.90, 2.51]
Comparison 2. Host immune functions
No. of No. of
1 Leukocyte 1 56 Mean Difference (IV, Random, 95% CI) 1.52 [0.59, 2.45]
2 NK activity 2 89 Std. Mean Difference (IV, Random, 95% CI) 0.45 [-1.60, 2.50]
3 CD3 4 213 Mean Difference (IV, Fixed, 95% CI) 3.91 [1.92, 5.90]
6 CD4/CD8 4 213 Mean Difference (IV, Fixed, 95% CI) 0.12 [0.01, 0.23]
Comparison 3. Quality of life
No. of No. of
1 Karnofsky score (dichotomous)) 3 284 Risk Ratio (IV, Fixed, 95% CI) 2.51 [1.86, 3.40]
2 Karnofsky score 1 29 Mean Difference (IV, Fixed, 95% CI) 12.70 [-4.72, 30.12]

Analysis 1.1. Comparison 1 Treatment response, Outcome 1 WHO criteria.
Review: Ganoderma lucidum (Reishi mushroom) for cancer treatment

Comparison: 1 Treatment response
Outcome: 1 WHO criteria
Study or subgroup G.lucidum Control Risk Ratio Weight Risk Ratio

n/N n/N IV,Fixed,95% CI IV,Fixed,95% CI
Gao 2003b 0/37 0/31 Not estimable
Yan 1998 23/35 9/21 87.5 % 1.53 [ 0.89, 2.65 ]
Zhang 2000 5/19 2/10 12.5 % 1.32 [ 0.31, 5.61 ]
Total (95% CI) 91 62 100.0 % 1.50 [ 0.90, 2.51 ]

Total events: 28 (G.lucidum), 11 (Control)
Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 1.56 (P = 0.12)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10

Favours control Favours G.lucidum
Analysis 2.1. Comparison 2 Host immune functions, Outcome 1 Leukocyte.

Comparison: 2 Host immune functions
Outcome: 1 Leukocyte
Mean Mean
Study or subgroup G.lucidum Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Yan 1998 35 -0.14 (1.315) 21 -1.66 (1.909) 100.0 % 1.52 [ 0.59, 2.45 ]
Total (95% CI) 35 21 100.0 % 1.52 [ 0.59, 2.45 ]

Heterogeneity: not applicable
-2 -1 0 1 2

Analysis 2.2. Comparison 2 Host immune functions, Outcome 2 NK activity.

Outcome: 2 NK activity
Std. Std.
Mean Mean
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Gao 2003b 32 18.7 (17.236) 28 -2.6 (9.601) 50.8 % 1.48 [ 0.90, 2.06 ]
Zhang 2000 19 -2.2 (6.102) 10 1.4 (4.8) 49.2 % -0.61 [ -1.40, 0.17 ]
Total (95% CI) 51 38 100.0 % 0.45 [ -1.60, 2.50 ]

Heterogeneity: Tau2 = 2.07; Chi2 = 17.78, df = 1 (P = 0.00002); I2 =94%
-4 -2 0 2 4
Analysis 2.3. Comparison 2 Host immune functions, Outcome 3 CD3.

Outcome: 3 CD3
Mean Mean
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Gao 2003b 37 9.6 (10.922) 31 3 (10.701) 14.9 % 6.60 [ 1.44, 11.76 ]
Leng 2003 30 7.534 (10.135) 30 4.03 (11.966) 12.6 % 3.50 [ -2.11, 9.11 ]
Yan 1998 35 5 (6.18) 21 -1.6 (5.325) 42.2 % 6.60 [ 3.54, 9.66 ]
Zhang 2000 19 -0.2 (5.021) 10 0.8 (4.557) 30.3 % -1.00 [ -4.62, 2.62 ]
Total (95% CI) 121 92 100.0 % 3.91 [ 1.92, 5.90 ]

Heterogeneity: Chi2 = 11.11, df = 3 (P = 0.01); I2 =73%
-20 -10 0 10 20


Outcome: 4 CD4
Mean Mean
Gao 2003b 37 2.1 (12.729) 31 2.3 (8.556) 16.4 % -0.20 [ -5.29, 4.89 ]
Leng 2003 30 9 (8.89) 30 0.5 (8.609) 21.6 % 8.50 [ 4.07, 12.93 ]
Yan 1998 35 4.7 (6.994) 21 -1.6 (5.966) 35.7 % 6.30 [ 2.85, 9.75 ]
Zhang 2000 19 1.8 (5.771) 10 5.6 (4.943) 26.3 % -3.80 [ -7.81, 0.21 ]
Total (95% CI) 121 92 100.0 % 3.05 [ 1.00, 5.11 ]

-20 -10 0 10 20


Outcome: 5 CD8
Mean Mean
Gao 2003b 37 -2.3 (9.706) 31 -10.4 (7.238) 20.2 % 8.10 [ 4.07, 12.13 ]
Leng 2003 30 1.633 (8.48) 30 -2.67 (6.147) 23.4 % 4.30 [ 0.55, 8.05 ]
Yan 1998 35 2.7 (6.022) 21 -1.8 (5.505) 34.5 % 4.50 [ 1.41, 7.59 ]
Zhang 2000 19 -1.5 (5.027) 10 8.4 (5.071) 21.9 % -9.90 [ -13.77, -6.03 ]
Total (95% CI) 121 92 100.0 % 2.02 [ 0.21, 3.84 ]

Heterogeneity: Chi2 = 49.05, df = 3 (P<0.00001); I2 =94%
-20 -10 0 10 20

Analysis 2.6. Comparison 2 Host immune functions, Outcome 6 CD4/CD8.

Outcome: 6 CD4/CD8
Mean Mean
Gao 2003b 37 0.2 (1.306) 31 -0.01 (1.047) 3.7 % 0.21 [ -0.35, 0.77 ]
Leng 2003 30 0.22 (0.236) 30 0.11 (0.237) 80.6 % 0.11 [ -0.01, 0.23 ]
Yan 1998 35 0.03 (0.503) 21 0.04 (0.587) 12.7 % -0.01 [ -0.31, 0.29 ]
Zhang 2000 19 0.2 (1.1) 10 -0.6 (0.608) 3.0 % 0.80 [ 0.18, 1.42 ]
Total (95% CI) 121 92 100.0 % 0.12 [ 0.01, 0.23 ]

-2 -1 0 1 2

Analysis 3.1. Comparison 3 Quality of life, Outcome 1 Karnofsky score (dichotomous)).

Comparison: 3 Quality of life
Outcome: 1 Karnofsky score (dichotomous))
Study or subgroup G.lucidum Control Risk Ratio Weight Risk Ratio

n/N n/N IV,Fixed,95% CI IV,Fixed,95% CI
Gao 2003b 16/37 4/31 9.4 % 3.35 [ 1.25, 8.99 ]
He 1997 91/100 18/60 59.6 % 3.03 [ 2.05, 4.49 ]
Yan 1998 24/35 9/21 31.0 % 1.60 [ 0.93, 2.75 ]
Total (95% CI) 172 112 100.0 % 2.51 [ 1.86, 3.40 ]

Total events: 131 (G.lucidum), 31 (Control)
Test for overall effect: Z = 5.97 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10

Analysis 3.2. Comparison 3 Quality of life, Outcome 2 Karnofsky score.

Comparison: 3 Quality of life
Outcome: 2 Karnofsky score
Mean Mean
Zhang 2000 19 -5.3 (19.584) 10 -18 (24.251) 100.0 % 12.70 [ -4.72, 30.12 ]
Total (95% CI) 19 10 100.0 % 12.70 [ -4.72, 30.12 ]

Heterogeneity: not applicable
-50 -25 0 25 50

ADDITIONAL TABLES
Table 1. Intervention combinations
Treatment arms versus Control arms
G. lucidum No intervention/placebo
G. lucidum + conventional Conventional
G. lucidum + CAM CAM
G. lucidum + Conventional + CAM Conventional + CAM

CAM: complementary and alternative medicine
APPENDICES
Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Neoplasms explode all trees
#2 (cancer* or carcinoma*or adenocarcinoma* or neoplasm* or tumor*or tumour*or malignan*) .mp.
#3 #1 or #2
#4 MeSH descriptor Ganoderma explode all trees
#5 (ganoderma* or lucidum* or reishi* or lingzhi* or ling zhi* or ling chih* or ling chi*) .mp.
#6 #4 or #5
#7 #3 and #6
Appendix 2. MEDLINE search strategy

1 exp ganoderma/
2 ganoderma.tw
3 reishi.tw
4 lingzhi.tw
5 “ling zhi”.tw
6 “ling chih”.tw
7 “ling chi”.tw
8 or/1-7
9 exp Neoplasms/
10 tumor*.tw
11 tumour*.tw
12 cancer*.tw
13 neoplas*.tw
14 carcinom*.tw
15 malignan*.tw
16 or/9-15
17 8 and 16
18 randomized controlled trial.pt
19 controlled clinical trial.pt
20 randomized.ab
21 placebo.ab
22 drug therapy.fs
23 trial.ab
24 groups.ab
25 or/18-24
26 humans.sh
27 25 and 26
28 17 and 27
Appendix 3. EMBASE search strategy

1. exp Ganoderma/
2. exp Ganoderma lucidum/
3. (ganoderma* or lucidum* or reishi* or lingzhi* or ling zhi* or ling chih* or ling chi*).mp.
4. 1 or 2 or 3
5. exp neoplasm/
6. (cancer* or carcinoma*or adenocarcinoma* or neoplasm* or tumor*or tumour*or malignan*).mp.
7. 5 or 6
8. 4 and 7
9. crossover procedure/
10. double-blind procedure/
11. randomized controlled trial/
12. single-blind procedure/
13. random*.mp.
14. factorial*.mp.
15. (crossover* or cross over* or cross-over*).mp.
16. placebo*.mp.
17. (double* adj blind*).mp.
18. (singl* adj blind*).mp.
19. assign*.mp.
20. allocat*.mp.
21. volunteer*.mp.
22. 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21
23. 8 and 22
Key:
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supple-
mentary concept, unique identifier
pt=publication type
ab=abstract
sh=subject heading
ti=title

Appendix 4. I/O form for primary studies
I/O form for Primary Studies
Study ID:
Reviewer:
Date:
Identification Details:
Author:
Year:
Journal Reference:
Source:
Digital Object Identifier (DOI):
On EndNote database: ..................................Yes/ No
Selection Criteria:
1. Study design is a RCT, not other designs........................................................... Yes/ No
2. The study concerns individual diagnosed with cancer.........................................Yes/ No
3. The study concerns Ganoderma Lucidum treatment.......................................... Yes/ No
4. The study concerns at least one of following outcomes...................................... Yes/ No
(Antitumor response/ immune system/ quality of life/ survival/ mortality/ adverse event)
Please tick only one box:
In Out Pending
Appendix 5. Standard extraction form for included studies

Study ID:
Reviewer:
Date:
1. General Information:
Authors:
Year:
Published:...................Yes/No
Title:
Journal Reference:
Publication Type:............................................ Full text/ Abstract
Language:.......................................English/ Chinese/ Japanese/ others ˙˙˙˙˙˙˙˙˙˙
Funding Source:
Author can be contacted for accessible data.......... Yes/ No
General information free text:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
2. Design Details:
2.1. Population:
Target Population:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Study Setting:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Total No. of Participants:
˙˙˙˙˙˙˙˙˙˙˙
Cancer Type:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Cancer Stage:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Diagnostic Criteria:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Inclusion and Exclusion Criteria:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
2.2. Interventions and Comparators:

No. of arms in this study: ˙˙˙
G. lucidum details (manufacturer, preparation, and dose):
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Interventions in experimental arm:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Interventions in control arms:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Free text comments on interventions:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
2.3. Outcomes:
Outcomes measured:
Tumour response............................................Yes/ No
Immune functions:
T lymphocytes.................................................Yes/ No
B lymphocytes.................................................Yes/ No
Macrophages..................................................Yes/ No
NK cell activity.................................................Yes/ No
Interleukins......................................................Yes/ No
TNF.................................................................Yes/ No
Quality of life...................................................Yes/ No
Survival/ Mortality............................................Yes/ No
Side effects.....................................................Yes/ No
Others:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Comments on outcomes measured:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
3. Data and Analysis

Statistical method for data analysis:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙
Subject data:

Intervention Group Control Group
No. Pre-specified
No. Assigned
% of Males
Mean Age
Median Age
No. Withdrawal from Baseline
No. Loss to Follow-up
No. Analyzed for Outcome Measure
Outcome data:
Intervention Group Control Group
Primary Outcomes:
Secondary Outcomes
(eg. Dichotomous data: 29/ 89; Continuous data: 89±12 unit)

Comments on data analysis:
˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙

Appendix 6. Risk of bias assessment form for included studies
Study ID:
Reviewer:
Date:
Adequate Sequence Generation: Judgement Description
Allocation Concealment:
Adequate Binding:
Incomplete Outcome Data Addressed:
Selective Outcome Reporting:
Free of Other Bias:
Summary of Bias:
Appendix 7. Criteria for judging risk of bias

Adequate sequence generation
Criteria for a judgement of “Yes”:
The investigators describe a random component in the sequence generation process such as:
• referring to a random number table,
• using a computer random number generator,
• coin tossing,
• shuffling cards or envelopes,
• throwing dice,
• drawing of lots,
• minimisation.
Criteria for a judgement of “No”:

Sequence generation process involves some systematic, non-random approach, for example:
• sequence generated by odd or even date of birth,
• sequence generated by some rule based on date (or day) of admission,
• sequence generated by some rule based on hospital or clinic record number.
Sequence generation process involves judgement or some method of non-random categorisation of participants, for example:
• allocation by judgement of the clinician,
• allocation by preference of the participant,
• allocation based on the results of a laboratory test or a series of tests,
• allocation by availability of the intervention.
Criteria for a judgement of “Unclear”:

Insufficient information about sequence generation process
Allocation concealment
Participants and investigators enrolling participants could not foresee assignment because a successful method of allocation concealment,
for example:
• central allocation (including telephone, web-based, and pharmacy-controlled, randomisation),
• sequentially numbered drug containers of identical appearance,
• sequentially numbered, opaque, sealed envelopes.

Participants and investigator enrolling participants could possibly foresee assignments and thus introduce selection bias, for example:
• using an open random allocation schedule (e.g. a list of random numbers),
• assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not
sequentially numbered),
• alternation or rotation,
• date of birth,
• case record number,
• any other explicitly unconcealed procedure.

Insufficient detail to permit judgement of “Yes” or “No”.
Adequate binding
Any one of the following:
• no blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by
lack of blinding,
• blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken,
• either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of
others unlikely to introduce bias.

• no blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding,
• blinding of key study participants and personnel attempted, but likely that the blinding could have been broken,
• either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

• insufficient information to permit judgement of “Yes” or “No”,
• the study did not address this outcome.
Incomplete outcome data addressed

• no missing outcome data,
• reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing
bias),
• missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups,
• for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a
clinically relevant impact on the intervention effect estimate,
• for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing
outcomes not enough to have a clinically relevant impact on observed effect size,
• missing data have been imputed using appropriate methods.

• reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing
data across intervention groups,
• for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce
clinically relevant bias in intervention effect estimate,
• for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing
outcomes enough to induce clinically relevant bias in observed effect size,
• ’as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation,
• potentially inappropriate application of simple imputation.
• insufficient reporting of attrition/exclusions to permit judgement of “Yes” or “No”,
• the study did not address this outcome.
Selective outcome reporting:
Any of the following:
• the study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the
review have been reported in the prespecified way,
• the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that
were prespecified (convincing text of this nature may be uncommon)
• not all of the study’s prespecified primary outcomes have been reported,
• one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were
not prespecified,
• one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as
an unexpected adverse effect),
• one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis,
• the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Insufficient information to permit judgement of “Yes” or “No”.
Free of other bias:
The study appears to be free of other sources of bias.
• there is at least one important risk of bias. For example, the study,
• had a potential source of bias related to the specific study design used, or
• stopped early due to some data-dependent process (including a formal-stopping rule), or
• had extreme baseline imbalance, or
• has been claimed to have been fraudulent, or
• had some other problem.
There may be a risk of bias, but there is either:
• insufficient information to assess whether an important risk of bias exists, or
• insufficient rationale or evidence that an identified problem will introduce bias
Summary of bias:
A - low risk of bias:
All criteria above met.
B - moderate risk of bias:
One or more or criteria only partly met.
C - high risk of bias
One or more criteria not met.

WHAT’S NEW
Last assessed as up-to-date: 4 February 2016.
Date Event Description
3 March 2016 New citation required but conclusions have not changed No new studies were identified for inclusion.
3 March 2016 New search has been performed Searches were updated in February 2016.
HISTORY
Protocol first published: Issue 2, 2009
Review first published: Issue 6, 2012
Date Event Description
23 February 2010 Amended 1. WHO Criteria for Tumour Response was added in the Primary Outcomes, as an alternative to
RECIST. The WHO criteria were frequently used in studies published by 2000
2. Details of handling treatment response data added in the ’Measures of treatment effect’
CONTRIBUTIONS OF AUTHORS
Xingzhong Jin: co-drafting the protocol and review, searching clinical trials, selection of trials, assessing quality of trials, data interpre-
tation.
Julieta Ruiz Beguerie: co-drafting the protocol and review, searching clinical trials, selection of trials, assessing quality of trials, data
interpretation.
Daniel Man-yeun Sze: searching and translating Chinese trials.
Godfrey CF Chan: co-drafting the protocol and review.
DECLARATIONS OF INTEREST
None of the authors is involved in clinical trials or have direct financial interest in the subject matter of this review.

SOURCES OF SUPPORT
Internal sources
• None, Other.
External sources
• None„ Other.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The WHO criteria for tumour response assessment was not included in the protocol and was added in the review stage, because it was
used in the trials that were conducted prior to the publication of the RECIST.
In the protocol, we predefined a strategy to cope with situations in which there were both dichotomous and continuous data for the
same single outcome of interest. We planned to convert the dichotomous data into continuous data by using the method introduced
in Section 9.4.6 of the Cochrane Handbook for Systematic Review of Interventions (Higgins 2011). During the review process, we were
concerned that combining two different types of data could misinterpret even biased results, thus we presented results pooled from
each type of data separately instead.
INDEX TERMS
Medical Subject Headings (MeSH)

Antineoplastic Agents [immunology; ∗ therapeutic use]; Immunity, Cellular [immunology]; Neoplasms [∗ drug therapy; immunology;
therapy]; Randomized Controlled Trials as Topic; Reishi [∗ chemistry]
MeSH check words

Humans


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Cochrane Database of Systematic Reviews

Jin X, Ruiz Beguerie J, Sze DMY, Chan GCF

Jin X, Ruiz Beguerie J, Sze DMY, Chan GCF.

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review)

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) i

Ganoderma lucidum (Reishi mushroom) for cancer treatment

Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

PLAIN LANGUAGE SUMMARY

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 2

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 3

1. Overall survival rate

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 4

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 5

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 6

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 7

2. Treatment response 3.2 NK-cell activity

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 8

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 9

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 10

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 11

Higgins 2003 WHO 1979

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 14

Characteristics of included studies [ordered by study ID]

Methods Randomised, double-blind, placebo-controlled, multicentre clinical trial

Interventions Ganopoly vs. placebo

Bias Authors’ judgement Support for judgement

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 15

Participants 160 various cancer patients (100 intervention, 60 control)

Interventions Lingzhi spore powder capsule + chemo/radiotherapy vs. chemo/radiotherapy

Outcomes QoL (Karnofsky score), blood count (WBC, Hb)

Bias Authors’ judgement Support for judgement

Participants 60 patients after colon cancer surgery

Interventions Zhengqing Lingzhi liquid vs. routine therapy

Outcomes T-cell subgroups, clinical symptoms

Bias Authors’ judgement Support for judgement

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 16

Allocation concealment (selection bias) Unclear risk No information of allocation concealment

Other bias Low risk No other sources of bias is found

Participants 56 patients non-parvicellular lung cancer

Interventions Laojunxian Lingzhi oral liquid + chemotherapy vs. chemotherapy alone

Outcomes WHO criteria, Karnofsky score, haematological parameters, T-cell subgroups

Bias Authors’ judgement Support for judgement

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 17

Participants 29 patients diagnosed as stage III or IV lung cancers

Interventions Lingzhi tablet vs. placebo

Bias Authors’ judgement Support for judgement

Other bias Low risk No other sources of bias is found

Ganoderma lucidum (Reishi mushroom) for cancer treatment (Review) 18

Study Reason for exclusion

Chen 2006 Non-randomised

Gao 2003a Non-randomised, non-controlled, before-after study

Gao 2004 Review

Gao 2005a Non-randomised, non-controlled, before-after study

Gao 2005b Non-randomised, open-labelled trial

Gill 2008 Non-randomised trial

Huang 2001 No outcome of interest

Jia 2005 Non-randomised trial

Jing 2007 Intervention consists of multiple herbal ingredients

Li 2000 Do not have outcomes of interest