CHAPTER THIRTEEN

Mushroom polysaccharide
lentinan for treating different
types of cancers: A review of
12 years clinical studies in China
Meng Zhanga,*, Yiran Zhanga, Lijuan Zhanga, Qingwu Tianb,*
a
Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University,
Qingdao, China
b
Clinical Laboratory, Affiliated Hospital of Qingdao University, Qingdao, China
*Corresponding authors: e-mail address: zmeng_ouc@163.com; qingwutian@sina.com

Contents
1. Introduction 299
2. Structure of lentinan 300
3. Biological mechanisms of lentinan 303
3.1 Immunostimulatory effect 303
3.2 Cytotoxicity 303
4. Preclinical and clinical studies of lentinan 303
4.1 Preclinical studies of combination of lentinan with chemotherapy and
targeted therapy 303
4.2 Clinical studies of lentinan 305
5. Concluding remarks 318
Acknowledgments 319
Conflicts of interest 319
References 319

Abstract
Lentinula edodes has been used to improve general health for thousands of years in Asia.
It is the second largest cultivated and the most popular edible mushroom in the world
known as “Xianggu” in China and “Shiitake” in Japan. Lentinan is a polysaccharide
extracted from Lentinula edodes. β-Glucan is the major bioactive component in lentinan
with immunostimulatory effect. The antitumor property of lentinan was reported in
1960s. Biochemical studies indicate that immunocytes can be activated by lentinan
through multiple signaling pathways, such as TLR4/Dectin1-MAPK and Syk-PKC-NFκB
pathways. Though it has been approved as an adjuvant therapeutic drug both in China
and Japan for treating cancers since 1980s, a systematic review of clinical studies of
lentinan has not been conducted elaborately. In this review, over 9474 reported
lentinan-associated cancer treatment cases are evaluated and summarized from 135

Progress in Molecular Biology and Translational Science, Volume 163 # 2019 Elsevier Inc. 297
ISSN 1877-1173 All rights reserved.
https://doi.org/10.1016/bs.pmbts.2019.02.013
298 Meng Zhang et al.

independent studies in China during the past 12 years (2004–2016) based on CNKI
(China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific
Journals Database) and Wanfang database. The 9474 reported lentinan-associated
cancer treatment cases include lung cancer (3469 cases), gastric cancer (3039 cases),
colorectal cancer (1646 cases), ovarian cancer (183 cases), cervical cancer (130 cases),
Non-Hodgkin lymphoma (70 cases), pancreatic cancer (15 cases), cardiac cancer (15
cases), nasopharyngeal cancer (14 cases), duodenal cancer (1 case) and 110 cancer cases
with no classifying patient information. Overall clinical data show solid effect of lentinan
on improving the quality of life and on promoting the efficacy of chemotherapy and
radiation therapy during cancer treatment.

Abbreviations
Drugs
5-Fu 5-fluorouracil
ADM adriamycin
CAPE capecitabine/xeloda
CBP carboplatin
CF leucovorin; calcium folinate
Chemo chemotherapy
CS cephalothin sodium
CTX adenosine cyclophosphate
DDP cisplatin; diamminedichloroplatinum
DXL docetaxel; taxotere
EPI epirubicin
FT tegafur/futrafur
GEM gemcitabine
IFO ifosfamide
L-OHP; OX oxaliplatin
MA megestrol acetate
MMC mitomycin
NDP nedaplatin
NVB vinorelbine
PDN prednisone
PTX paclitaxel; taxinol
S-1 tegafur gimeracil oteracil
THP pirarubicin
VCR vincristine
VP-16 etoposide
YS yanshu injection
Drug combinations for chemo
CAF CTX + ADM + 5-Fu
CAP CTX + ADM + DDP
CF CF + 5-Fu
CFOXFT CF + L-OHP + FT
CHOP CTX + ADM/THP + VCR + PDN
Lentinan for treating cancers 299

DCF DXL + DDP + 5-Fu

DF DXL + 5-Fu
DOX DXL + L-OHP
DP DXL + DDP
ECF EPI + DDP + 5-Fu
ELF VP-16 + CS + 5-Fu
ELFP VP-16 + CS + 5-Fu + DDP
EOF EPI + L-OHP + 5-Fu
EOX EPI + L-OHP + CAPE
EP VP-16 + DDP
FAC 5-FU + ADM + CTX
FOLFOX CF + 5-Fu + L-OHP
FOLPCF CF + PTX + DDP + 5-Fu
FP 5-Fu + DDP
FTP FT + DDP
GP GEM +DDP
IEP IFO + VP-16 + DDP
LFP CF + 5-Fu + DDP
MAFP MMC + ADM + 5-Fu + CBP
MATP MA + PTX + DDP
MFP MMC + 5-Fu + DDP
NOX NVB + L-OHP
NP NVB + DDP
OF L-OHP + 5-Fu
PC CBP + PTX
PCF PTX + DDP + 5-FU
PF PTX + 5-Fu
PN PTX + NDP
SOX S-1 + L-OHP
SP S-1 + DDP
TA PTX + ADM
TACE EPI + MMC + CBP
TP PTX + DDP
XELOX L-OHP + CAPE
XrayDP X-ray + DXL + DDP

1. Introduction
The medicinal qualities of Shiitake mushrooms have been known
for thousands of years in China.1,2 The antitumor property of lentinan
was reported by Chihara et al.3 Lentinan is mainly composed of β-glucan
with therapeutic properties such as antitumor, anti-inflammatory,4 and
anti-diabetes properties,5 etc. Lentinan was approved as an adjuvant for
300 Meng Zhang et al.

stomach cancer therapy in Japan in 1985. It is approved for treating multiple

types of cancer as well as for hepatitis and other diseases. Lentinan is available
as capsules, tablets, and injections. Clinical data show that lentinan is a bio-
logical response modifier and an immunostimulant with proven efficacy in
treating hepatitis,6,7 HIV,8 malignant pleural effusion9,10 and cancers.11,12
This article will review clinical applications of lentinan in treating lung can-
cer during the past 12 years in China and data are available in the CNKI, VIP
and Wanfang databases in which lentinan has been applied as an adjuvant
therapy to chemotherapy.

2. Structure of lentinan
There have been numerous reports on structures and components in
lentinan, but only β-glucan has been established to be associated with immu-
nologic competence.13 The primary structure of β-glucan in lentinan was
demonstrated by Sasaki and Takasuka,14 which is consisted of β-(1-3)-
glucose backbone with (1-6)-β-glucose branches of every two glucose
units15 (Fig. 1). Though β-glucans are common, the biological activities
vary greatly due to different structures (Table 1). The secondary structure
of β-glucan in lentinan is a single helical conformation confirmed by
13
C-NMR.15 Surenjav et al.21 studied four types of polysaccharides
extracted from Lentinus edodes (fruiting body). All of them are β-glucans con-
taining 4.6–15.2% proteins and displaying antitumor activities. However,
the activity is reduced after the polysaccharides are processed by ultrasound
and deproteinization. This indicates that secondary structure, relative
molecular mass, and the associated proteins may also affect the antitumor
activities of lentinan.

Fig. 1 A schematic diagram of β-glucan structure in lentinan.

Table 1 Structure of glucan from different sources.
Solubility
Source Backbone Branching in water Biological activity
Bacteria None/α-1,4 or α-1,6 Insoluble Anti-
inflammation,16
Antithrombin17

Fungus Short β-1,6 branching Insoluble Immunoregulation18

Continued
Table 1 Structure of glucan from different sources.—cont’d
Solubility
Source Backbone Branching in water Biological activity
Yeast Long β-1,6 branching Insoluble Anti-oxidant19

Cereal None Soluble Lowering

cholesterol20

Update from Wikipedia, Beta-Glucan. https://en.wikipedia.org/wiki/Beta-glucan (accessed 2018-05-28 21:29:00).

Lentinan for treating cancers 303

3. Biological mechanisms of lentinan

3.1 Immunostimulatory effect
Studies22 show that β-glucan as the main component of lentinan plays a key
role in immunoregulation of lentinan. It can trigger downstream signaling,
such as MAPK-NFκB and Syk-PKC, through binding with pattern recog-
nition receptors (TLR2/4/6/9, Dectin-1, etc.), complement receptor
(CD11b), and other membrane receptors,23 which activates the function
of immunocytes (NK, macrophage, T cells).24,25 Peng et al.26 used lentinan
(self-made) to stimulate mouse spleen lymphocytes and the results showed
that the expression of both TLR4 and TLR9 are up-regulated initially in
addition to up-regulated TNF-α expression by T-lymphocytes. Wang
et al.27 reported that lentinan (Zhejiang Fangge Pharmaceutical CO.,
LTD) promotes IgG secretion by B-lymphocytes and enhances phagocytic
activity of macrophages in mice. In 1988, P
eter et al.28 showed that lentinan
(self-made) activates natural killer cells (NK) and induces antibody-dependent
cell-mediated cytotoxicity (ADCC) in vitro. Additionally, Kupfahl et al.29
reported that pre-treatment of mice with lentinan (self-made) results in
increased concentrations of TNF-α, IL-12 and IFN-γ (Fig. 2). Yoshino S.
et al.30 found that the percentage of CD4+ IFN-γ + T-cell increases signif-
icantly (P < 0.05) whereas the percentages of CD4+ IL-4+ T-cell and CD4+
IL-6+ T-cell decrease significantly (P < 0.02) in patients’ blood with digestive
cancers after intravenous administration of lentinan, which indicates that
lentinan can change the Th2-dominated environment of cancer patients to
help maintain the balance of Th1 and Th2 cells.
3.2 Cytotoxicity
Lentinan can also possessed direct cytotoxicity on tumor cells. Bao et al.
proved that lentinan could trigger apoptosis through intracellular reactive
oxygen species (ROS) in treating human bladder cancer T24 cells.31 Sim-
ilarly, it has been reported that lentinan induced cytotoxicity on S180 cells
via mitochondria pathways by up-regulating Bax and down-regulating
Bcl-2, which resulted in apoptosis of S180 cells.32

4. Preclinical and clinical studies of lentinan

4.1 Preclinical studies of combination of lentinan with
chemotherapy and targeted therapy
Lentinan has been proved to function as a biological response modifier
(BRM) during preclinical pharmacological studies.33–35 It exhibits a great
304 Meng Zhang et al.

TLR4
SIGNR1 Dectin-1 Scavenger

CR3 LacCer

syk PI3K
Akt
MyD88
MAPK MIP2
Card9 TRAF-6
NFAT PKC
iC3

NFκB
P65/50

Macrophage
DC cell
Monocyte

Cytokine
(TNF-α, IL-2,
IL-10, IL-12)

NK cell B cell

T cell

Humoral immunity

Adaptive immunity
Fig. 2 Immunostimulating and immunobalancing effects of β-glucan. Immunocytes
can be activated by β-glucan through binding with membrane receptors, such as
pattern recognition receptors (TLR4, Dectin-1), complement receptor (CD11b), etc.
Subsequently, downstream signaling pathways, MAPK-NFκB and Syk-PKC-NFκB, are
involved in immunoregulation.
Lentinan for treating cancers 305

potential to boost immune response to tumor burden. Oncologists realize

that such an effective but low toxic immunomodulator is an ideal agent
to combine with chemotherapeutics due to the severe side effect and immu-
nosuppressive environment caused by chemo. For treating non-small cell
lung cancer (NSCLC), lentinan was found to be synergistic with paclitaxel
by activating TXNIP-NLRP3 inflammasome through ASK1/p38 MAPK
signal pathway.36 Cisplatin is the first-line drug in treating advanced lung
cancer; however, nephrotoxicity is the troublesome caused by cisplatin.
A new study showed that lentinan significantly prevented cis-DDP-induced
kidney injury in vivo through activation of the NRF2-ARE signaling
pathway.37
Furthermore, targeted therapies that specifically inhibit the growth of
cancer cells have been developed greatly.38,39 HER2 is a member of the
ErbB family that plays an important role in promoting oncogenic transfor-
mation and tumor growth.40 Herceptin (trastuzumab) has been successfully
used in treating HER2 overexpressed breast cancer patients.41 An in vivo
study clearly demonstrated lentinan to significantly suppress tumor growth
combined with Herceptin in BT474 xenografts in nude mice.42 Consider-
ing that approximately 18–33% NSCLC tumors, 17–42% adenocarcinomas,
and 2–40% large-cell carcinomas lung cancer, as well as 22.1% in gastric
cancer are HER2 positive,43,44 the synergistic action with targeting cancer
therapy might be expected when lentinan is used in combination with anti-
bodies plus cytotoxic chemotherapeutic agents for patients with more HER-2
positive cancers.

4.2 Clinical studies of lentinan

Lentinan is clinically widespread used in treatment of cancer in both China
and Japan. As a drug, lentinan can be taken both orally and intravenously.
Commonly, 1–2 mg lentinan is recommended by Chinese Food and Drug
Administration (SFDA) for intravenous infusion. Here, we mainly summa-
rize clinical use of lentinan to treat lung cancer, and data were collected from
the reported cases in the past 12 years in China (Fig. 3).
Response rates (RR) known as common evaluation indicator of tumor
treatment is the sum of complete response (CR) and partial response (PR).
Response rate for Chemo (C) or Chemo + lentinan (C + L) treated patients
are summarized in Table 2 for lung cancer, Table 3 for gastric cancer,
Table 4 for digestive system cancers, Table 5 for gynecological, breast
cancers, and lymphoma, and Table 6 for multiple cancers. Although the
306 Meng Zhang et al.

Fig. 3 Lentinan used as adjuvant drugs in treating different cancers. Over 68.69%
lentinan treatments were given to lung (3469 cases, 36.62%) and gastric (3039 cases,
32.08%) cancer patients. “Colorectal” group include colon (892 cases, 9.42%), colorectal
(472 cases, 4.98%), and rectum (282 cases, 2.98%) cancers. “Gynecologic” group is
composed of ovarian cancer (183 cases, 1.93%) and cervical cancer (130 cases, 1.37%).
“Others” group is composed of Non-Hodgkin lymphoma (NHL, 70 cases, 0.74%), pancre-
atic cancer (15 cases, 0.16%), cardiac cancer (15 cases, 0.16%), nasopharyngeal cancer
(NPC, 14 cases, 0.15%), duodenal cancer (1 case, 0.01%) and 110 cancer cases with no
classifying data.45

123 independent studies set different standards in defining response rate,

all chemotherapy plus lentinan groups exhibited better efficacy and
response rates than chemotherapy groups (Tables 2–6). For example,
the reported overall response rates in chemotherapy plus lentinan groups
for lung cancer, gastric cancer and hepatic cancer are 29.0–88.7%,
11.1–87.5%, and 50.7–76.0%, respectively, compared to 15.0–83.3%,
30.6–71.0% and 31.8–52.0% in chemotherapy groups. More importantly,
Karnofsky performance status (KPS) that is used to evaluate quality of life
and physical condition for patients shows significant improvement after
treatment with lentinan. Thus, the alleviation of adverse effects, such
as leukopenia, thrombocytopenia and vomiting, etc., caused by chemo-
therapy is the major role played by lentinan during the course of cancer
treatment.
Although the side effect of lentinan is rare, some clinical cases were
reported (Table 3). Low blood pressure, allergy, urgent appeal, and dizzy
were major side effects. Usually, these symptoms would relieve within
15–30 min after drug withdraw, oxygen uptake, intravenously given
10 mg dexamethasone, or intravenously given 10 mL 10% calcium gluco-
nate. These cases indicate that more observation during nursing is required
for the drug that have not been tested for anaphylaxis in advance, and only
that can avoid serious consequences in time.
Table 2 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with lung cancer.
Group drugs (C + L)/C (%)
Cases (M/F) Age KPS C cases (M/F) used C + L cases (M/F) Group drugs used response rate References
112(75/37) 35–71
60 56(38/18) XrayDP 56(37/19) L + XrayDP 88.7/83.3 46
60(39/21) 55  3
70 30(20/10) GP 30(19/11) L + GP 86.7/76.7 47
46(29/17) 59 m

50 20(12/8) DDP 26(17/9) L + DDP 84.6/55.0* 48
140(78/62) 60–85 60–80 70(38/32) GP/TP 70(40/30) L + GP/TP 82.9/62.9* 49
49 N/A
50 26 EP 23 L + EP 76.9/39.1* 50
104(54/50) 33–73 N/A 52(27/25) NP 52(27/25) L + NP 71.2/44.2* 51
86(44/42) N/A 60–100 42(25/17) NP 44(28/16) L + NP 70.5/69.0 52
98(65/33) 60  13 N/A 49(34/15) GP 49(31/18) L + GP 69.4/55.1* 53
139(80/59) 60–86 60–80 70(38/32) TP/GP 69(42/27) L + TP/GP 66.7/60.0 54
87(57/30) 66  14 N/A 46(32/14) EP 41(25/16) L + EP 65.9/43.5* 55
68(42/26) 25–78 60–90 34 GP 34 L + GP 64.7/47.1 56
62(38/24) 38–69
60 31(18/13) GP 31(20/11) L + GP 64.5/38.7* 57
61(39/22) 39–74 67.7  9.4 30(20/10) GP 31(19/12) L + GP 64.5/36.7* 58
66(37/29) N/A
60 32(18/14) DP 34(19/15) L + DP 61.7/31.2* 59
65(51/14) 43–71 N/A 32(26/6) CAP + CE 33(25/8) L + CAP + CE 57.6/34.4* 60
231(146/85) 60  14 >60 105(68/37) GP 126(78/48) L + GP 57.1/40.0 61
Continued
Table 2 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with lung cancer.—cont’d
Group drugs (C + L)/C (%)
Cases (M/F) Age KPS C cases (M/F) used C + L cases (M/F) Group drugs used response rate References
52(31/21) 45–78 N/A 22(13/9) GP 30(18/12) L + GP 56.7/54.5* 62
52(37/15) 55–75
70 26(20/6) PC 26(17/9) L + PC 53.8/42.3 63
63(38/25) 43–71
50 31 NP 32 L + NP 53.1/48.4 64
68 32–74
70 34 GP/NP/TP 34 L + GP/NP/TP 52.9/44.1 65
100(72/28) 25–80 N/A 50 Chemo 50 L + Chemo 52.0/28.0* 66
90(62/28) 75
60 45(30/15) GP/NP/DP 45(32/13) L + GP/NP/DP 51.1/28.9* 67
76(51/25) 40–60 50–70 38(25/13) MATP 38(26/12) L + MATP 50.0/47.4 68
78(66/12) 34–71
60 26(22/4) NOX 52(44/8) L + NOX 50.0/46.1 69
81(65/16) 18–60 60–80 39(32/7) NP 42(33/9) L + NP 50.0/33.3* 70
98(64/34) 26–78 70–90 49 GP 49 L + GP 49.0/40.8 71
70 32–72
70 35 GP/NP/DP 35 L + GP/NP/DP 48.6/40.0 72
64(55/9) 35–69 60–100 31(27/4) NP 33(28/5) L + NP 48.5/35.5 73
61(45/16) 65–85 60–100 29(22/7) NP 32(23/9) L + NP 46.9/34.5 74
69 N/A
60 34 GP 35 L + GP 45.7/41.2 75
68(39/29) 35–76
70 35 PC 33 L + PC 45.5/45.7 76
113(68/45) 42–76
70 56 DP 57 L + DP 43.9/37.5 77
80(58/22) 33–74
60 40(30/10) NP 40(28/12) L + NP 42.5/45.0 78
82(63/19) 51  4 >60 42(33/9) GP 40(30/10) L + GP 42.5/41.5 79
86(55/31) 43–72
60 43(26/17) DP 43(29/14) L + DP 37.2/16.3* 80
71(50–21) 26–74 N/A 36(26/10) GP 35(24/11) L + GP 37.1/36.1 81
51(29/22) 56–58 m
>60 26(14/12) GP 25(15/10) L + GP 36.0/34.6 82
80(53/27) 18–70
70 40(28/12) DP 40(25/15) L + DP 30.0/15.0* 83
31(26/5) 65–80 >60 – – 31(26/5) L + GEM 29.0 84
80(43/37) 40–78
60 40 GP 40 L + GP N/A 85
N/A: Not available; m: median; *P < 0.05, Student’s t-test.
Table 3 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with gastric cancer.
Group drugs Group drugs (C + L)/C (%)
Cases (M/F) Age KPS C cases (M/F) used C + L cases (M/F) used response rate References
80(49/31) 55–80 >70 40(24/16) DCF 40(25/15) L + DCF 87.5/75.0 86
74(51/23) 26–70
70 38(25/13) FOLFOX 36(26/10) L + FOLFOX 83/71* 87
60(45/15) 28–72
70 30(23/7) CAPE 30(22/8) L + CAPE 83/70* 88
78(48/30) 25–67 >60 39 PCF 39 L + PCF 74.4/46.2* 89
m
60(52/9) 54–55 60–80 30(25/5) PCF 30(26/4) L + PCF 73/5* 90
75(42/33) 53  11
70 37 FOLFOX 38 L + FOLFOX 67.6/44.7* 91
116(64/52) 45–71 N/A 56(31/25) FOLFOX 60(33/27) L + FOLFOX 65.0/55.4 92
220(167/53) 26–73 N/A 110 FOLFOX 110 L + FOLFOX 64.6/32.7* 93
62(34/28) 48–75 >70 31 XELOX 31 L + XELOX 64.5/42.0* 94
77(40/37) 37–75 >70 39 FOLFOX 38 L + FOLFOX 64.1/39.5* 95
36(21/15) 47–70
70 17(10/7) SP 19/(11/8) L + SP 63.2/47.1* 96
37(27/10) 24–77 N/A 18(14/4) EOX 19(13/6) L + EOX 63.1/50.0** 97
68(42/26) N/A >70 34(20/14) FOLFOX 34(22/12) L + FOLFOX 61.7/32.4* 98
66(46/20) 30–75
60 30 ECF 36 L + ECF 61.1/36.7* 99
80(48/32) 25–70 >60 40 PCF 40 L + PCF 60/37.5** 100
112(87/25) 65–81
70 56(43/13) CFOXFT 56(44/12) L + CFOXFT 60.7/41.1* 101
38(27/11) 36–70 >60 – – 38(27/11) L + ELFP 57.9 102
39(29/9) 28–76
60 – – 39(29/9) L + SOX 52.6 103
52(28/24) 44–71 N/A 25(13/12) FOLFOX 27(15/12) L + FOLFOX 51.9/45.0 104
72(45/27) 35–74 >80 37 FAC 35 L + FAC 51.4/51.4 105
72(49/23) 32–72 80 37 DF 35 L + DF 51.4/48.7 106
66(43/23) 27–70
70 34(21/13) FOLPCF 32(22/10) L + FOLPCF 50/47.1 107
80(56/24) 26–72 N/A 36 PF 38 L + PF 50/38 108
40(25/15) 18–70 >80 15(10/5) DOX 25(15/10) L + DOX 48/40 109
62(36/26) 29–72
60 30 ECF 32 L + ECF 46.9/40.0 110
30(20/10) 40–65 N/A 15 PCF/DCF 15 L + PCF/DCF 46.7/33.3 111
86(48/38) 40–78 >70 43 FOLFOX 43 L + FOLFOX 46.5/44.2 112
79(52/27) 26–65 >60 79(52/27) L + S-1 45.6 113
74(42/32) 65–82 N/A 36 S-1 38 L + S-1 36.8/30.6 114
27(18/9) 70–89 N/A 27(18/9) L + S-1 11.11 115
80(45/35) 26–75 N/A 40(22/18) Chemo 40(23/17) L + Chemo N/A 116
44(25/19) 34–75 N/A 22(13/9) DCF 22(12/10) L + DCF N/A 117
32(22/11) 42–78 >50 17 ELF 15 L + ELF N/A 118
60(39/21) N/A N/A 30 FOLFOX 30 L + FOLFOX N/A 119
44(26/18) 25–74
60 22 PF 22 L + PF N/A 120
90(48/42) 42–69
70 45(25/20) XELOX 45(23/22) L + XELOX N/A 121
N/A: Not available; m: median; **P < 0.01, *P < 0.05, Student’s t-test.
Table 4 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with digestive system cancers.
Group Group drugs (C + L)/C (%)
Cases (M/F) Age KPS Types of cancer C cases (M/F) drugs used C + L cases (M/F) used response rate References
90(53/37) 51–70 N/A Colon 45(26/19) FOLFOX 45(27/18) L + FOLFOX 93.3/84.4* 149
48(33/15) 41–72 N/A Colon 24(16/8) XELOX 24(17/7) L + XELOX 83.3/41.7* 150
120(68/52) 39–73 N/A Colon 60(32/28) XELOX 60(36/24) L + XELOX 78.3/63.3* 151
60(37/23) 59  4 N/A Colon 30(18/12) XELOX 30(19/11) L + XELOX 63.3/33.4* 152
63(35/28) 32–74
60 Colon 31(16/15) FOLFOX 32(19/13) L + FOLFOX 56.3/41.9* 153
124(84/40) 38–72 N/A Colon 61(41/20) XELOX 63(43/20) L + XELOX 55.6/31.2** 154
72(48/24) 27–78 >60 Colon 34(23/11) FOLFOX 38(25/13) L + FOLFOX 39.5/38.2 155
62(40/22) 30–72
70 Colon 30(20/10) LFP 32(20/12) L + LFP N/A 156
45(26/19) 41–73 N/A Colorectal 22 FOLFOX 23 L + FOLFOX 69.6/40.9* 157
50 (26/24) 38–71 N/A Colorectal 24(12/12) XELOX 26(14/12) L + XELOX 58/42 158
78(47/31) 63  8
60 Colorectal 37(23/14) FOLFOX 41(24/17) L + FOLFOX 34/29.7 159
65 (51/14) 43–71 N/A Colorectal 32(26/6) FOLFOX 33(25/8) L + FOLFOX N/A 160
40(22/18) 35–72 N/A Colorectal 20 FOLFOX 20 L + FOLFOX N/A 161
68(41/27) 55  14 N/A Colorectal 41(25/16) LFP 27(16/11) L + LFP N/A 162
60(29/31) 52–68 >90 Esophageal 30(13/17) FP 30(16/14) L + FP N/A 163
27(15/12) 45–80
60 Rectum 27(15/12) L + FOLFOX 70.4 164
69(46/23) 60–92
60 Rectum 31 FOLFOX 38 L + FOLFOX 47.4/41.9 165
45 (28/17) 35–70 >60 Hepatic 23(15/8) PF 22(13/9) L + PF 65.2/31.8 166
50(32/18) 37–74 N/A Hepatic 25 MAFP 25 L + MAFP 76.0/52.0* 167
146(120/26) 20–74 N/A Hepatic 71 TACE 75 L + TACEH 50.7/33.8 168
172(90/82) 28–76 >60 Gastric 58 86 Chemo 86 L + Chemo 77.1/46.5* 169
Colorectal 114
63(47/16) 60–80 >60 Gastric 45 31(24/7) PF 32(23/9) L + PF 65.6/45.2* 170
Colon 12
Rectum 6
128(71/57) 60–82 60–80 Colon 61 65 FOLFOX 63 L + FOLFOX 63.1/58.5 171
Rectum 67 or XELOX or XELOX
108(56/52) 26–72 >60 Gastric 50 54(27/25) DP 54(29/27) L + DP 58.9/40.4 172
Intestinal 58 CFOXFT L + CFOXFT
54(30/24) 26–72
70 Gastric 21 11 DCF 10 L + DCF 58.6/40.0* 173
Intestinal 33 14 FOLFOX 19 L + FOLFOX
50(43/7) 60–85 N/A Gastric 17 25(20/5) Chemo 25(23/2) L + Chemo 36.0/28.0 174
Colon 33
78(51/27) >62 <50–80 Hepatic 11 40 YS 38 L + YS 31.6/10.0* 175
Intestinal 27
Gastric 20
Esophageal 15
Pancreatic 5
82(50/32) 26–85 >60 Colon 46 42(30/12) 5-FU 40(20/20) L + 5-FU N/A 176
Rectum 36
N/A: Not available; **P < 0.01, *P < 0.05, Student’s t-test.
Table 5 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with gynecological, breast cancers, and lymphoma.
Types of C cases Group C + L cases Group drugs (C + L)/C (%)
Cases (M/F) Age KPS cancer (M/F) drugs used (M/F) used response rate References
60(0/60) 33–64
80 Breast 30 Chemo 30 L + Chemo 83.3/40.0 122
52(0/52) 25–78
60 Breast 24 TA 28 L + TA 67.9/62.5 123
15(0/15) 31–74 N/A Breast 15 L + DDP 80.0 124
80(0/80) 51  13
70 Ovarian 40(0/40) TP 40(0/40) L + TP N/A 125
93(0/93) 65–79 60  7 Ovarian 41(0/41) TP 52(0/52) L+ TP 84.6/53.7* 126
40(0/40) N/A N/A Cervical 20(0/20) TP 20(0/20) L + TP 65.0/60.0 127
90(0/90) 47  6 >70 Cervical 45(0/45) DP 45(0/45) L + DP 55.6/44.4 128
60(34/26) 7–72 N/A NHL 28 CHOP 32 L + CHOP 87.5/67.9* 129
N/A: Not available; *P < 0.05, Student’s t-test.
NHL, Non-Hodgkin lymphoma.
Table 6 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with multiple cancers.
Types of Group drugs C + L cases Group drugs (C + L)/C (%)
Cases (M/F) Age KPS cancer C cases (M/F) used (M/F) used response rate References
129(72/57) 63–75
50 Gastric 61 51(30/21) Chemo 78(42/36) L + Chemo 64.1/48.4* 177
Lung 36
Esophageal 22
Other cases 10
49(26/23) 20–69
60 Breast 2 24 NP 25 L + NP 64.0/29.2* 178
Ovarian 1 CAP L + CAP
Hepatic 5 MFP L + MFP
Gastric 17 FP L + FP
Intestinal 6 FP L + FP
NSCLC 15 NP L + NP
SCLC 3 CVP L + CVP
41(27/14) 26–68 50–100 Gastric 15 20 FP 21 L + FP 61.9/30.0 179
Hepatic 4 MFP L + MFP
Small FP L + FP
intestinal 6 EP L + EP
SCLC 2 CAP L + CAP
NSCLC 14
Continued
Table 6 Response rate for chemo (C) or chemo + lentinan (C + L) treated patients with multiple cancers.—cont’d
Types of Group drugs C + L cases Group drugs (C + L)/C (%)
Cases (M/F) Age KPS cancer C cases (M/F) used (M/F) used response rate References
86(52/34) <30 to >60 N/A Esophageal 3 38 CF 48 L + CF 52.1/34.2* 180
Gastric 7 CF L + CF
Colon 15 CF L + CF
NSCLC 19 NP L + NP
SCLC 20 IEP L + IEP
Breast 22 FAC L + FAC
NHL 10 CHOP L + CHOP
90(45/35) 18–68
60 Lung 25 45(27/18) NP/GP/FP 45(28/17) L + NP/GP/FP 51.1/28.9* 181
Breast 13 CAF/TA L + CAF/TA
Esophageal 12 FP L + FP
NPC 14 DDP + PF L + DDP + PF
Colorectal 11 FOLFOX/ L + FOLFOX/
Pancreatic 6 XELOX XELOX
Ovarian 9 GP L + GP
GAP/TP L + GAP/TP
50(25/25) 45–66 N/A Gastric 21 25(12/13) EOF 25(13/12) L + EOF 48.0/32.0* 182
NSCLC 19 PN L + PN
Colon 10 OF OF
418 65–68m 70–90 Gastric 218 200(147/53) FOLFOX 218 L + FOLFOX 45.9/38.0 183
(314/104) Lung 16 (167/51)
Esophageal 69
Colon 61
Rectum 70
67(50/17) 54–84 >60 Gastric 21 33 FOLFOX 34 L + FOLFOX 41.2/39.4 184
Lung 1
Esophageal 9
Colon 15
Colorectal 1
Rectum 7
Hepatic 8
Pancreatic 4
Small
intestine 1
Duodenal 1
100(76/24) 28–68
70 Lung 50(37/13) NP 50(39/11) L + NP 38.0/20.0* 45
NPC FP L + FP
Gastric FOLFOX L + FOLFOX
Colorectal FOLFOX L + FOLFOX
Pancreatic GP L + GP
Breast CAF L + CAF
Ovarian CAP L + CAP
52(32/20) 52  7 N/A Esophageal 37 26 FTP 26 L + FTP N/A 185
Cardiac 15
N/A: Not available; m: median; *P < 0.05, Student’s t-test.
NSCLC, Non-small cell lung cancer; SCLC, Small cell lung cancer; NHL, Non-Hodgkin lymphoma; NPC, Nasopharyngeal cancer.
318 Meng Zhang et al.

Table 7 Lentinan-associated adverse reactions in cancers.

Cases
(M/F) Age Adverse events References
1(0/1) 51 Low blood pressure 130
14(8/6) 36–82 Low blood pressure, allergic shock 122
1(1/0) 51 Chest tightness, palpitation, dyspnea, blurred mind, 131
hypotension
1(1/0) 56 Allergy, fever, annihilation 132
1(0/1) 56 Chest tightness, annihilation, cold sweat, hypotension 133
1(1/0) 62 Shiver, chest tightness 134
1(1/0) 70 Rash 135
1(1/0) 76 Polypnea, increased blood pressure, backache 136
1(0/1) 82 Cyanotic on lips, chest tightness, annihilation, 137
obnubilation, wheezing, sinus tachycardia
2(0/2) 36–56 Headache, palpitation, chest tightness, flushed face, 138
rash, pruritus
2(1/1) 62–87 Nausea, vomiting, panidrosis, chest tightness, 139
annihilation, pressure in the chest
3(1/2) 46–56 Dizzy, low blood pressure, chilly 140
3(3/0) 53–61 Shock, rash, leucocytopenia 141

In the reported 9474 lentinan treatment cases, 18 cases are associated with
adverse events (Table 7). The clinical manifestations are allergy, skeletal
muscle injury, acute asthma, rash, shock, dizzy, and trembling, etc. All these
side effect are observed in 60 min after lentinan infusion and the fastest
adverse reaction happened in 2 min.142 The symptoms are eased in 30 min
with drug withdrawal. Glucose solution or 0.9% sodium chloride solution
is usually used to dilute lentinan before infusion. Whether using other solu-
tion as dilution medium would increase incidence of adverse effect is not
clear, mixing lentinan with other drugs for injection is strictly prohibited.143

5. Concluding remarks
This article briefly introduced the structure, molecular mechanisms of
lentinan. Edible mushrooms have been used as a traditional herbal medicine
in China for thousands of years and it is well known to enhance body’s
Lentinan for treating cancers 319

immunity. Pharmacological studies show that lentinan is the major biolog-

ical component in mushrooms. Clinical data published in the past 12 years
show solid effect of lentinan on improving quality of life and on promoting
the efficacy of chemotherapy and radiation therapy during cancer treatment.
Though, lentinan showed cytotoxicity on cancer cells in vitro, it mainly
functions as a biological response modifier and the ability of immunoregu-
lation has drawn more attraction to oncologists and pharmacologists.
Imbalance of Th1/Th2 and immunosuppressive tumor microenvironment
caused by chemo have been found to be an important reason for failure of
chemotherapy.144,145 Accordingly, chemoimmunotherapy has developed a
lot in order to overcome shortage of chemotherapy.146,147 Glycan-based
drugs, such as lentinan, are potential and ideal immunoregulating drugs
combined with chemotherapeutics due to their broad spectrum of therapeu-
tic properties, relatively low toxicity, and low costs. As a matter of fact, a
phase III study comparing therapy using S-1/lentinan with S-1 alone is
now under-way in Japan.148 These clinical experiences may be great helpful
to treat lung cancer in future and to make full use of lentinan for cancer
patients worldwide.

Acknowledgments
This research was supported by the Natural Science Foundation of China (Grant 81672585),
Key Technology Fund of Shandong Province (Grant 2016ZDJS07A07), the Taishan Scholar
Fellowship, the “Double First Class fund” of Shandong Province in China to L.Z., and
Postdoctoral application research project in Qingdao China (Grant 40518060042) to M.Z.

Conflicts of interest
The authors declare no conflict of interest.

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