572883
research-article2015
ICTXXX10.1177/1534735415572883Integrative Cancer TherapiesFritz et al
Original Article
Polysaccharide K and Coriolus versicolor Extracts for Lung Cancer: A Systematic Review
Integrative Cancer Therapies 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735415572883 ict.sagepub.com
Heidi Fritz, ND, MA1, Deborah A. Kennedy, MBA, ND, PhD1,2, Mami Ishii, BM, MT-BC1, Dean Fergusson, PhD3, Rochelle Fernandes, MSc1,2, Kieran Cooley, ND1,2, and Dugald Seely, ND, MSc, FABNO1,3,4
Abstract Background. Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. Methods. We searched PubMed, EMBASE, CINAHL, the Cochrane Library, AltHealth Watch, and the Library of Science and Technology from inception to August 2014 for clinical and preclinical evidence pertaining to the safety and efficacy of PSK or other Coriolus versicolor extracts for lung cancer. Results. Thirty-one reports of 28 studies were included for full review and analysis. Six studies were randomized controlled trials, 5 were nonrandomized controlled trials, and 17 were preclinical studies. Nine of the reports were Japanese language publications. Fifteen of 17 preclinical studies supported anticancer effects for PSK through immunomodulation and potentiation of immune surveillance, as well as through direct tumor inhibiting actions in vivo that resulted in reduced tumor growth and antimetastatic effects. Nonrandomized controlled trials showed improvement of various survival measures including median survival and 1-, 2-, and 5-year survival. Randomized controlled trials showed benefits on a range of endpoints, including immune parameters and hematological function, performance status and body weight, tumor-related symptoms such as fatigue and anorexia, as well as survival. Although there were conflicting results for impact on some of the tumorrelated symptoms and median survival, overall most randomized controlled trials supported a positive impact for PSK on these endpoints. PSK was safely administered following and in conjunction with standard radiation and chemotherapy. Conclusions. PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted. Keywords cancer, complementary and alternative medicine, Coriolus versicolor, herb-drug interactions, lung cancer, natural health products, polysaccharide K (PSK), polysaccharide peptide (PSP), systematic review
Introduction Lung cancer is the second most commonly diagnosed cancer, and the leading cause of cancer mortality resulting in approximately 150 000 deaths per year in the USA over the past decade.1 More than 50% of lung cancer cases are diagnosed at the advanced stages of the disease, with poor prognosis and a 5-year survival rate less than 5%.1 It is crucial to identify new adjuvant treatment strategies that might improve outcomes for this disease. Natural medicines are used by up to 54% of patients with lung cancer and deserve to be examined more closely for their potential to affect therapeutic outcomes as well as overall quality of life.2 PSK, also known as polysaccharide K or Krestin, is a protein-bound polysaccharide or “proteoglycan”3 that has
been used in Japan for more than 30 years as an adjunctive immunotherapy for a variety of cancer types, including lung cancer.3,4 PSK was first isolated in 1971 from the mushroom Coriolus versicolor (also known as Trametes versicolor or Yun Zhi), and has since been studied in Japan for its effects when used in combination with standard surgery, 1
Canadian College of Naturopathic Medicine, Toronto, Ontario, Canada The University of Toronto, Toronto, Ontario, Canada 3 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada 4 Ottawa Integrative Cancer Centre, Ottawa, Ontario, Canada 2
Corresponding Author: Dugald Seely, Ottawa Integrative Cancer Centre, 29 Bayswater Ave, Ottawa, Ontario, K1Y 2E5, Canada. Email: [email protected]
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chemotherapy, and radiation therapy.3,4 Controlled human trials have documented extended survival times associated with use of PSK in various cancer types, including breast,5 colorectal,6 and other gastrointestinal cancers,7 but PSK has not been comprehensively reviewed for its effect in lung cancer specifically.3 The structure of PSK consists of a polypeptide moiety to which polysaccharide β-d-glucan chains are attached; approximately 62% of the molecule is polysaccharide and 38% is protein.3 PSP (polysaccharide peptide) is a closely related protein-bound polysaccharide derived from the same mushroom, and has also been studied for applications in cancer. The 2 polysaccharides are differentiated based on the presence of fucose in the PSK molecule, while rhamnose and arabinose are present in PSP; in other respects the 2 polysaccharides are chemically similar.8 This review includes evidence for both PSK and PSP since both are Coriolus extracts. Like interleukins, interferons, and colony stimulating factors, PSK is a nonspecific immunotherapy, meaning that it is used to “augment the body’s natural immune response without directing it against any specific tumor antigen.”4 In the literature, PSK is also referred to as a biological response modifier, which is a substance that improves the “host versus tumor response”4 and increases the ability of the host to defend itself from tumor progression. Immunologically, this may involve potentiation of natural killer (NK) cell and lymphocyte-activated killer (LAK) cell activity.4 PSK may also be useful in offsetting some of the hematological side effects of chemotherapy such as leucopenia, thrombocytopenia, or pancytopenia. Although promising results have been reported in clinical trials, there has been no knowledge synthesis of PSK or C versicolor for use in lung cancer. We conducted a systematic review of the safety and efficacy of PSK/C versicolor for the treatment and prevention of lung cancer.
Methods We searched the following electronic databases for all levels of evidence pertaining to PSK and lung cancer: PubMed, EMBASE, CINAHL, AltHealthWatch, the Cochrane Library, and the National Library of Science and Technology, from inception to the end of October 2009. The PubMed search was updated to the end of August 2014. We used a broad-based MeSH and keyword approach combining clinical (lung cancer) and therapeutic (PSK) search terms. We hand searched bibliographies of review articles for additional references. Separate searches were conducted independently by the first and second authors (HF and DAK). Table 1 provides details on the search terms and strategy used to collect the records for screening from both searches employed. Figure 1 provides a flowchart of the searches.
Table 1. Search Strategy. Search Strings PSK OR polysaccharide K OR Krestin OR polysaccharide K* OR polysaccharopeptide OR PSP OR Coriolus versicolor
AND Lung Neoplasma OR Chemoprevention
a
“Lung neoplasm” was the MeSH term used in PubMed; in other databases, “Lung cancer” was used.
We piloted data extraction forms in duplicate to assess inter-researcher reliability. On completion of data extraction in duplicate for fifty percent of human level studies, there were no major inconsistencies, and further duplication of data extraction was found to be redundant. Extraction sheets were prepared partly based on the Consolidated Standards of Reporting Trials (CONSORT) statement,9,10 the NewcastleOttawa scale (NOS),11 and the Score for Assessment of Physical Experiments on Homeopathy (SAPEH)12 for human trials, observational studies, and preclinical studies, respectively. For randomized controlled trials, quality assessment was performed according to the Jadad scoring system.13 Screening of studies was initially conducted based on title review. In the event of uncertainty, abstracts and/or full texts were also reviewed. English language publications were included for all levels of evidence. Since the majority of human studies for PSK have been conducted in Japan, Japanese language publications were included if they reported controlled human trials; data for these was extracted by the third author (MI). Human trials had to assess the efficacy of PSK or other C versicolor preparations in lung cancer for the purposes of treatment, primary or secondary prevention, reduction of side effects and toxicities associated with chemotherapy or radiation therapy, or assessment of potential interactions with these therapies. All types of lung cancers (small cell lung cancer, non–small cell lung cancer, mesothelioma) were included. For inclusion, preclinical studies had to be conducted in lung cancer models and examine either PSK or other C versicolor preparations for their anticancer effects or their interaction with conventional chemo- or radiation- therapy. Preclinical studies were categorized by results as positive, negative, neutral, or mixed. The term positive designates studies that found significant anticancer effects from PSK in models of lung cancer, alone or additively with other agents; negative designates studies that found significant procarcinogenic effects alone or in combination with other agents; and neutral designates studies that found neither significant beneficial effect nor any evidence of harm. In the absence of reported levels of significance, the authors’ interpretation was used to guide classification.
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Fritz et al
214 records selected for initial screening for efficacy in Lung Cancer articles
167 records excluded after deduplication and initial title/ abstract review
47 full text articles screened
16 records excluded - 3 Reviews - 13 Not relevant to PSK and lung cancer, not related to treatment effects, non-English preclinical studies, or a duplication of data
31 Articles included for Data Extraction and Analysis - 15 Reports of 11 controlled human trials - 7 reports of 6 RCTs - 8 reports of 5 non-randomized controlled trials - 0 Observational Studies - 17 Preclinical studies (1 included in RCT report)
Figure 1. Literature flowchart.
Results The combined searches provided 214 records for screening. Fifteen reports of 11 controlled human trials14-28 and 17 preclinical studies29-44 were included in the efficacy analysis. One randomized controlled trial article also included the report of an animal study, for a total of 31 articles. Nine of the 15 reports were Japanese language publications.18-20,22-27 Figure 1 shows a flowchart of the literature search and study selection.
Preclinical Evidence Of the 17 included preclinical studies, 15 supported the anticancer effects of PSK. Two studies showed no significant effects and no studies found harmful or negative effects. Seven of the 17 supported immune mediated antitumor activity including tumor cell lysis by NK and LAK cells; seven supported antimetastatic activity; six supported anticancer effects in vivo by decreasing tumor size or incidence of cancer after carcinogen exposure; five supported the ability of PSK to increase survival in vivo; two studies supported antiproliferative effects; one study supported
proapoptotic effects; and five supported general improvement in immune function by way of increased cell counts and cytokine levels as well as preventing chemotherapyinduced immune suppression. There was no evidence of PSK having a procarcinogenic effect. Table 2 summarizes the preclinical evidence.21,29-44 Immunologic Activity and Chemotherapy-Induced Immune Suppression. In vivo administration of PSK was able to abolish the decrease in phagoctyic activity and the number of Kupffer cells otherwise induced by the chemotherapeutic agents 1-2-tetrahydrofuryl-5-fluorouracil (FT) and 5-fluorouracil (5-FU).41 In other lung cancer models, PSK increased the concentrations of lymphocytes, macrophages, and neutrophils in bronchoalveolar lavage fluid and induced synthesis of TNF-α, IL-1α, IL-6, MIP-1α, and MIP-1β31; normalized splenic NK activity33; and increased the numbers of CD8+ CD4− T cells and CD4+ CD8− T cells in the thymus.39 Immune-Mediated Antitumor Activity. Ishihara et al,32,33 Ueno et al,42 and Vanky et al,44 found that PSK increased the antitumor cytotoxicity of various immune cells, including neutrophils, NK cells, and lymphocytes. PSK increased neutrophil mediated cytotoxicity and increased NK cell mediated lysis of tumor cells, prolonging survival and decreasing metastasis32,33 and increased the antitumor activity of splenic LAK cells and tumor infiltrating lymphocyte (TIL) cells.42 In vitro, PSK at clinically attainable levels augmented the cytotoxicity of NK cells and large granular lymphocytes (LGLs) taken from lung cancer patients against various cancer cells.37 Similar effects were found when using lymphocytes and target cancer cells taken from untreated lung (and other) cancer patients.36 In animals, PSK administered within 48 hours of birth was found to significantly increase mean survival time up to 189% when animals were subsequently transplanted with lung cancer cells (P < .001); CD8+ T cells were thought to be the effector cells since blockade of CD8+ cell activity inhibited this effect.39 Nonspecific Antitumor Effect. Ito et al34 found that PSK reduced tumor growth in vivo, but mechanisms were not examined. Katoh and Ooshiro38 found that PSK alone in high doses was able to inhibit lung tumor growth, but there was no additive effect in combination with uracil/tegafur/ leucovorin chemotherapy. Metastasis. Ishihara et al31 found that PSK given to a model of lung metastasis significantly reduced the number of lung nodules (P < .001) and increased the cytostatic activity of bronchoalveolar cells (P < .05) compared with controls. Further studies by the same team found similar effects, as well as reduced weight loss in the treated animals.32,33 Matsunaga et al40 found that PSK significantly reduced the
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number of metastases and increased survival time compared with control animals (P < .05) through inhibition of tumor cell adhesion to membrane, degradation of collagen IV, chemotaxis of tumor cells, and haptotaxis to fibronectin.40 In splenectomized animals treated with FT and 5-FU chemotherapy, PSK was able to offset the metastasis promoting effects of these drugs.41 In combination with chemotherapy, PSK augmented the effect of cyclophosphamide and IL-2, suppressing lung metastasis, and increasing survival.42 Following thoracic surgery, PSK nonsignificantly improved survival and decreased lung metastasis.29,30 When administered postoperatively with both surgical tumor removal and cyclophosphamide chemotherapy, PSK reduced lung metastasis compared with either cyclophosphamide or PSK alone.43 Proliferation and Apoptosis. PSK significantly (P < .001) reduced proliferation of A549 lung cancer cells up to 80%; produced cell cycle arrest; increased the percentage of apoptotic cells in part by increasing expression of capsase 3; and increased peripheral blood lymphocyte (PBL) proliferation 4.5-fold over control (P < .01) when combined with IL-2.35
Nonrandomized Controlled Trials There were eight reports of five nonrandomized controlled trials for the treatment of lung cancer.16-18,22,23,25-27 This category includes studies for which no randomization was reported as well as studies that explicitly stated that randomization was not used. Often the treating physician’s clinical judgment as to which treatment would most benefit the particular patient was the deciding factor when choosing between several treatments, including chemotherapy alone, chemotherapy and PSK, chemotherapy and OK-432 (a bacterial-derived immunotherapy), or chemotherapy and both PSK and OK-432. In three of the five trials, PSK plus chemotherapy and/or radiation was compared with chemotherapy and/or radiation alone. In two trials, PSK was given without concurrent chemotherapy, and in one of these, PSK was given to stages I to III patients who had responded to previous radiation therapy.16,17 Median Survival. All five studies used measures of survival as endpoints. Significantly increased median survival was reported with use of PSK among stage 0 to 1 non–small cell lung cancer patients who had responded to radiation 16, 17 ; in patients receiving PSK, OK-432, or both as immunotherapy in addition to chemotherapy or radiation therapy.23 One study found no difference between treatment with immunotherapy (PSK, OK-432, or Tegafur) plus chemotherapy compared to chemotherapy alone,22 and one study reported increased median survival associated with use of PSK but did not provide a measure of significance for the finding.18
One-,Two-, and Five-Year Survival. One study reported significantly increased 5-year survival in patients receiving PSK following radiotherapy compared with no adjunctive therapy, 30% compared with 9% (P < .001), and two studies failed to report significance. Other studies reported no significant effect for PSK alone, but significantly increased 1-year survival associated with combined use of both PSK and OK-432 compared with no adjunctive therapy (P < .025).18 Ogawa et al25-27 and Kawamura et al22 reported increased survival at 1 and 2 years associated with use of either PSK or OK-432, or both, but did not report significance. Hayakawa et al16,17 found that use of PSK among patients with stage III disease increased their 2-year survival such that it was superior to that of stages I and II patients who received chemotherapy without PSK, 43% versus 26%, respectively (P < .05).
Randomized Controlled Trials There were seven reports of six randomized controlled trials of PSK or PSP for the treatment of lung cancer.14,15,19-21,24,28 All the randomized controlled trials involved administration of 3 g/d of PSK or PSP alongside standard chemotherapy, with the exception of the study by Tsang et al28 during which PSP was given for 28 days following chemotherapy. All six studies showed benefit on at least one of the following endpoints: parameters of immune function, body weight, performance score, tumor-related symptoms, or survival. Tables 3 and 4 provide a description of the design and outcomes of the included studies.14-28 Immune Function. PSK was found to shorten the duration of bone marrow suppression associated with chemotherapy,20,21 and beneficially increased white blood cell counts,15,21,28 hemoglobin,15 platelets,21 neutrophils,28 IgG and IgM,28 NK cell activity,14 IL-1,14 IL-2,15 and CD4/CD8 ratio and/or CD4 counts.14,15 Two of 3 studies found that PSP significantly increased or stabilized body weight compared with control patients receiving chemotherapy alone.14,15,28 Performance Status and Body Weight. Two of three studies found that PSP or PSK was able to significantly improve performance status.14,15,24 One study found no significant effect on tumor response rates or tumor-associated symptoms, but found that the PSK group had significantly fewer study withdrawals due to progressive disease, 5.9% compared with 23.5% in the control group (OR = 4.9, 95% CI = 1.0-25.5, P = .04).28 Cancer-Associated Symptoms. Two of three studies found significant patient-reported improvements in tumor-related symptoms including fatigue, loss of appetite, nausea and vomiting, dry mouth and throat, spontaneous or night
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5
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y
Kariya et al36
5
—
11
y
y
y
y
—
y
—
—
y
y
y
y
y
y
y
y
—
41
30 in LuCa arm
52
41
—
8 per group
—
—
NR
NR
30
18
60
56
120 in LuCa arm
45 in LuCa arm
—
n
CY
—
OK-432
—
MMC; IFN, IL-2
5-FU FT
IFN, IL-2
—
CY w/w/o IL-2
—
Carboplatin, etoposide
—
—
—
—
UFT/LV
—
6
—
y
—
—
—
—
—
—
—
y
y
y
—
—
y
y (PSK alone)
—
5
—
—
NS
—
—
—
—
—
y
y
y
y
—
—
y
n
—
2
—
—
—
—
—
—
—
—
—
n
y
—
—
—
—
—
y
1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
y
7
y (w chemo)
—
—
n
—
y (w chemo)
—
—
y
y
—
y
y
y
—
—
—
7
—
—
—
—
y
y
y
y
y
—
—
y
—
y
—
—
—
5
—
—
—
—
—
y
—
y
—
—
y
y
y
—
y
—
—
Anticancer Immune-Mediated Effect Effect on Immune ↑Survival/ Effect (↓Lung ↓Mortality/ System Apart From Antiproliferative Antimetastatic/ on Tumor (↑ Tumor Tumor Incidence/ ↑Time to Tumor Effect/Growth Proapoptotic Angiogenic/ Cell Lysis/Cytotoxicity Effect on Tumor Chemotherapy Multiplicity/Volume) Development by Immune Cells) (↑ No. Immune Cells) Inhibition Effect Invasive Effecta
Outcomes Measured and Effects
↑ NK lytic activity
PSK + CY following surgical removal of primary tumor markedly ↓ lung colony formation compared to either agent alone
—
Nonsignificant tendency to ↑survival with PSK
NS ↓ in lung mets
MMC did not abrogate the effect of PSK; IFN augmented effect of PSK in certain LΦ subsets; IL-2 had no effect on PSK’s action
PSK abolished the ↓in phagocytic activity, number of Kupffer cells, and thymus weight cz’d by 5-FU and FT
PSK augments NK cell cytotoxicity independently of IFN and IL-2
—
PSK augmented effect of CY
↓ Chemotaxis, adhesion to membrane, and degradation of collagen IV
Significantly better effect when PSK combined w chemo c/t chemo alone
↑ TNF-α, superoxide ions in NΦ
↑ TNF-α, IL-1α, IL-6, MIP1α, β; ↑ LΦ, MΦ, NΦ
—
PSK alone ↓ tumor volume, but no additive effect w UFT/LV
—
Note
15 + 2n 0–
+
+
n
n
+
+
+
+
+
+
+
+
+
+
+
+
+
+ /−/ n / m
Abbreviations: 5-FU, 5 fluorouracil; CY, cyclophosphamide; FT, a derivative of 5-fluorouracil; IFN, interferon; IL-2, interleukin 2; LΦ, lymphocyte; LV, leucuovorin; MΦ, macrophages; MMC, mitomycin C; NΦ, neutrophils; NK, natural killer cells; OK-432, a bacterial-based immunotherapy used commonly in Japan; UFT, tegafur/uracil; w/w/o with or without. “+” results in favor of PSK; “−” detrimental results found with PSK use; “n” no significant effect or neutral result; “y” yes effect demonstrated; — not applicable/outcome not assessed. a Includes effects on tumor growth observed in animal models of metastasis to the lungs, such as that induced by intravenous or subcutaneous injection of lung cancer cells, as well as results from in vitro on markers such as vascular endothelial growth factor or invasive capacity. Thus, results from animal models of metastasis are differentiated from effects on primary tumor growth induced by administration of carcinogen, and are detailed under this column, whereas measures of (nonmetastatic) primary tumor growth are categorized under “Anticancer Effect.”
Total
Usui et al
43
—
—
Tsuru et al41
Ito et al34
y
Kariya et al37
—
y
Vanky et al44
—
—
Ueno et al42
Hattori et al29
y
Matsunaga et al40
Hattori et al30
—
—
Ishihara et al32
Katoh21
—
—
Ishihara et al33
Ishihara et al31
—
Matsunaga et al39
y
In Vitro In Vivo
—
35
Katoh et al38
Jiménez-Medina et al
Reference
Design
Table 2. Preclinical Evidence.
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Age, y
NR
M 351 F 134
NR
NR
Liu et al (1999)15
Liu et al (1993)14
M 89 F 18
NR
Range 33 to 88
NR
Matsushima et al (1980)23
Ogawa et al (1981, 1982a, 1982b)25-27
NR
NR
NR
PS
NR
KPS 100 to 50
PS 0-3
PS 0-2
NR
Stage III and IV SCLC and NSCLC
NR
Most stage III or IV, NSCLC NR
Stage III or IV SCLC or NSCLC
Stage I-IV
Stage I-III NSCLC patients who responded to radiation therapy
Stage III and IV NSCLC (adenocarcinoma)
Stage I-IV NSCLC
PSK 3 g/d with or w/o rG-CSF 75 µg/d plus carboplatin + etoposide chemotherapy (mean 4.7 cycles) PSP 3g/d ×2 mo plus standard chemotherapy or radiotherapy according to cancer type PSP 3060 mg/d + shark liver extract 450 mg/d ×2 mo plus chemotherapy according to cancer type
PSP 3060mg/d following six 3-wk cycles of paclitaxol + carboplatin
Intervention
NR
NR
NR
NR
Radiation therapy
Patients received one or more of the following in combination: 1. PSK 3 g/d 2. OK-432 5 KE 2×/wk 3. Tegafur 600 mg/d All group could also receive chemo and radiation therapy 1. PSK 3 g/d ×3 d/wk (cycles) 2. OK-432 bacterial immunotherapy 2.0 KE/d IM 3 d/wk 3. Both PSK and OK-432 1. PSK 3 g/d 2. OK-432, dose NR Both with chemo or radiation therapy 3. PSK plus OK-432 + chemo/radiation therapy 1. PSK dose NR 2. OK-432 dose NR 3. Both concurrently with chemo and radiation therapy
PSK 3 g/d as intermittent dosing: 2 wk on, 2 wk off
Surgical removal 1. PSK 3 g/d starting 2 wk after surgery of lung cancer + chemotherapy with one of several regimens as determined by the clinician (VCR, MMC, MTX, EX, 5-FU) 2. OK-432 1-2 to 5 KE 2 d/wk every 2 wk No previous PSK 3 g/d plus vindesine/cisplatin therapy chemotherapy
Karnofsy Chemo, PS ~86 radiation, (mean) and/or surgery in most Stage II-IV SCLC or PS 0-3 Lobectomy in NSCLC most, radiation in some Esophageal cancer, n = 223 NR NR Stomach cancer, n = 230 Lung cancer, n = 197 Stage I to IV: KPS ≥ 60 NR Esophageal cancer, n = 162 Stomach cancer, n = 152 Lung cancer, n = 171
Stage III or IV inoperable NSCLC
Staging
Previous Chemo or Surgery
“Long term” until progression or death
NR
2y
2 mo
2 mo
NR
28 d
NR
2-4 y depending on disease progression
Chemo and “As long as radiation possible” only (no immunotherapy)
Chemo or radiation therapy only (no immunotherapy)
No treatment
Chemo and Up to 32 mo radiation therapy only
No adjuvant therapy
Chemotherapy only
Chemotherapy only
placebo + chemo or radiation therapy Placebo + chemotherapy
Carboplatin + etoposide only
paclitaxol + carboplatin only
Control
Treatment Duration
NR
Enrollment: 19992001 follow-up:
172
107
172
38
188
138
113
At least 5 years between Jan 1975 and December 1979
NR
5y
1979-1988: 9 y
Enrollment: 19761989 (13y) follow-up: till December 1994
June 1986 to May 1989: 3 y
July 1979to December 1982: 3.5 y
650 April 1996 to (197 lung) September 1997: 18 mo 485 February to July (171 lung) 1992: 6 mo
14
68
Sample Size Study Duration
n
n
n
n
n
n
n
y
y
n
NR
n
n
n
n
n
y
y
y
y
y
y
n
n
n
n
n
y
n
n
n
n
y
—
—
—
—
—
3
1
3
1
1
5
Dropout JADAD Score /LTFU Blinding Random Reported (RCTs)
Abbreviations: CA, cancer; CAD, coronary artery disease; comb, combination; f/u, follow-up; GI, gastrointestinal; LTFU, loss to follow-up; NR, not reported; NSCLC, non–small cell lung cancer; pop, population; PS, performance score; SCLC, small cell lung cancer; w, with.
M 142 F 30
NR
NR
M 124 F 18
M 31 F7
NR
NR
NR
NR
NR
NR
M 93 F 45
Median 60 Hiyoshi et al (1981) (range 3018 80+) Nippon
Japanese language Kawamura Range 40-89 et al (1990)22
NR Nishiwaki et al (1990)24 Nonrandomized trials English language Hayakawa et Over half of patients al (1993, ≥70 1997)16,17
Japanese language 70 M 79, F 34 Ikeda et al (1986)19
M 11, F 3
Mean 59
M 132, F 480
Gender
Katoh et al (1998)20,21
Randomizd controlled trials English language Tsang et al T group 61; C group 55 (2003)28 (mean)
Reference
Smokers/ Asbestos Exposure
Population
Table 3. Methodologies of Human Trials.
7
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—
—
—
—
Tsang et al (2003)28
Katoh et al (1998)21,22
Liu et al (1999)15
Liu et al (1993)14
Stage IV group, Months
—
—
—
—
OK432 12.2; Both 14.4; Control 7.5 PSK 7.6 OK432 7.0; Both 5.0; Control 3.3 Immunotherapy No 8.3 mo immunotherapy 3.8 mo — —
PSK 9.0
OK-432 28; Tegafur 19
PSK 19
—
13.5 12
—
300 d 457 d 265 d
30 15.5
301 d 576 d 255 d
—
—
—
—
—
P < .05
NR
NR
NR
P < .001 P = 0.38
—
NS P =.075 NS
P < .01
P < .01
NR
—
—
—
—
P Value
Measure
T
—
—
—
—
—
—
—
—
—
—
—
PSK 11 CR 12 PR 0 PD 4 DS —
—
—
9.5 (all no PSK) 14/93 34/93 45/93
Other
—
—
C 0 CR 0 PR 5 PD 20 DS
—
—
—
—
—
—
—
—
—
—
Control 18 CR 13 PR 0 PD 16 DS —
No./total: 31/135 52/139 58/135 60/139 46/135 27/139
20.5 (all PSK) No. / total: 38/95 26/95 31/95
0 CR O PR 4 PD 25 DS
—
—
—
Tumor response
Change in body weight: ↑≥1 kg Stable ↓≥1 kg
Time to recurrence (mo) Change in body weight: ↑ Stable ↓
Tumor response
Other T
C
—
—
—
—
—
—
—
—
—
—
—
NR
—
—
—
—
—
—
—
—
All Stage3 Stage4
—
—
—
45
—
—
—
—
P Value
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
16.9% 17.9% P = 1.00 37.5% 11.1% P = .046 6.4% 22.5% P = .058
—
—
—
Effectivenessa
85.5
—
—
Measure
—
Respiratory Pain Fatigue Weight loss —
No change c/t/b
T
Stage 4
Stage 3
—
Stage IV patients
Stage III patients
All patients
—
—
26%
OK-432 100%; Control 85.7% OK-432 68.4%;Control 44.5% —
OK-432 82.1%; Control 61.8%
—
P Value
Measure
4-y survival all patients
—
NR
—
SCC patients: Stage 0-1 Stage 2-3
5-y survival All patients
—
P < .10 trend Stage I c/t in active control P < .01 Stage III
NR
17.8%
PSK, OK-432 or Both: 48.4%
—
PSK 15.4%
5.6%
None 25%
—
OK-432 16.7%; Both 25.0%; Control 5.6%
NR
NR
NR
—
Sign improvement c/t/b
T ↓WBC+ neutrophils c/t/b
—
—
Survival at 65 mo (5.5y)
—
—
17% 4%
9%
OK-432 NR; Control 61.2% OK-432 35.0%; Control11.1% —
OK-432 36.7% Control 34.7%
4- or 5-y Survival
—
7/52
—
—
—
1/55
—
—
—
P Value
Measure
NR
—
—
—
—
P < .05 P < .005
P < .001
—
P < .1 trend c/t in active control P < .01 c/t in active control
NR
T
KPS: ↑ Stable ↓
—
—
—
—
—
—
—
—
—
Score 0 1 to 2
—
—
—
7/93 65/93 21/93
—
P < .05
P=.04 OR 4.9 95%CI 1.025.5 —
P Value
—
—
—
—
—
—
—
—
N = 15 56
—
—
—
—
—
—
—
—
—
—
—
N= 9 58
—
—
—
Performance Score
—
—
—
—
—
—
—
—
P = .333
—
—
—
No./total: 40/135 P = .0031 62/139 81/135 72/139 14/135 5/139
No. / total: 12/96 79/96 5/96
—
23.5%
C
Performance Score
Withdrawals 5.9% d/t DP
P < .001 for KPS: both, P < .05 ↑≥10 Stable ↓>10
P < .01 for all
“Tendency”
p
research-article2015
ICTXXX10.1177/1534735415572883Integrative Cancer TherapiesFritz et al
Original Article
Polysaccharide K and Coriolus versicolor Extracts for Lung Cancer: A Systematic Review
Integrative Cancer Therapies 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735415572883 ict.sagepub.com
Heidi Fritz, ND, MA1, Deborah A. Kennedy, MBA, ND, PhD1,2, Mami Ishii, BM, MT-BC1, Dean Fergusson, PhD3, Rochelle Fernandes, MSc1,2, Kieran Cooley, ND1,2, and Dugald Seely, ND, MSc, FABNO1,3,4
Abstract Background. Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. Methods. We searched PubMed, EMBASE, CINAHL, the Cochrane Library, AltHealth Watch, and the Library of Science and Technology from inception to August 2014 for clinical and preclinical evidence pertaining to the safety and efficacy of PSK or other Coriolus versicolor extracts for lung cancer. Results. Thirty-one reports of 28 studies were included for full review and analysis. Six studies were randomized controlled trials, 5 were nonrandomized controlled trials, and 17 were preclinical studies. Nine of the reports were Japanese language publications. Fifteen of 17 preclinical studies supported anticancer effects for PSK through immunomodulation and potentiation of immune surveillance, as well as through direct tumor inhibiting actions in vivo that resulted in reduced tumor growth and antimetastatic effects. Nonrandomized controlled trials showed improvement of various survival measures including median survival and 1-, 2-, and 5-year survival. Randomized controlled trials showed benefits on a range of endpoints, including immune parameters and hematological function, performance status and body weight, tumor-related symptoms such as fatigue and anorexia, as well as survival. Although there were conflicting results for impact on some of the tumorrelated symptoms and median survival, overall most randomized controlled trials supported a positive impact for PSK on these endpoints. PSK was safely administered following and in conjunction with standard radiation and chemotherapy. Conclusions. PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted. Keywords cancer, complementary and alternative medicine, Coriolus versicolor, herb-drug interactions, lung cancer, natural health products, polysaccharide K (PSK), polysaccharide peptide (PSP), systematic review
Introduction Lung cancer is the second most commonly diagnosed cancer, and the leading cause of cancer mortality resulting in approximately 150 000 deaths per year in the USA over the past decade.1 More than 50% of lung cancer cases are diagnosed at the advanced stages of the disease, with poor prognosis and a 5-year survival rate less than 5%.1 It is crucial to identify new adjuvant treatment strategies that might improve outcomes for this disease. Natural medicines are used by up to 54% of patients with lung cancer and deserve to be examined more closely for their potential to affect therapeutic outcomes as well as overall quality of life.2 PSK, also known as polysaccharide K or Krestin, is a protein-bound polysaccharide or “proteoglycan”3 that has
been used in Japan for more than 30 years as an adjunctive immunotherapy for a variety of cancer types, including lung cancer.3,4 PSK was first isolated in 1971 from the mushroom Coriolus versicolor (also known as Trametes versicolor or Yun Zhi), and has since been studied in Japan for its effects when used in combination with standard surgery, 1
Canadian College of Naturopathic Medicine, Toronto, Ontario, Canada The University of Toronto, Toronto, Ontario, Canada 3 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada 4 Ottawa Integrative Cancer Centre, Ottawa, Ontario, Canada 2
Corresponding Author: Dugald Seely, Ottawa Integrative Cancer Centre, 29 Bayswater Ave, Ottawa, Ontario, K1Y 2E5, Canada. Email: [email protected]
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chemotherapy, and radiation therapy.3,4 Controlled human trials have documented extended survival times associated with use of PSK in various cancer types, including breast,5 colorectal,6 and other gastrointestinal cancers,7 but PSK has not been comprehensively reviewed for its effect in lung cancer specifically.3 The structure of PSK consists of a polypeptide moiety to which polysaccharide β-d-glucan chains are attached; approximately 62% of the molecule is polysaccharide and 38% is protein.3 PSP (polysaccharide peptide) is a closely related protein-bound polysaccharide derived from the same mushroom, and has also been studied for applications in cancer. The 2 polysaccharides are differentiated based on the presence of fucose in the PSK molecule, while rhamnose and arabinose are present in PSP; in other respects the 2 polysaccharides are chemically similar.8 This review includes evidence for both PSK and PSP since both are Coriolus extracts. Like interleukins, interferons, and colony stimulating factors, PSK is a nonspecific immunotherapy, meaning that it is used to “augment the body’s natural immune response without directing it against any specific tumor antigen.”4 In the literature, PSK is also referred to as a biological response modifier, which is a substance that improves the “host versus tumor response”4 and increases the ability of the host to defend itself from tumor progression. Immunologically, this may involve potentiation of natural killer (NK) cell and lymphocyte-activated killer (LAK) cell activity.4 PSK may also be useful in offsetting some of the hematological side effects of chemotherapy such as leucopenia, thrombocytopenia, or pancytopenia. Although promising results have been reported in clinical trials, there has been no knowledge synthesis of PSK or C versicolor for use in lung cancer. We conducted a systematic review of the safety and efficacy of PSK/C versicolor for the treatment and prevention of lung cancer.
Methods We searched the following electronic databases for all levels of evidence pertaining to PSK and lung cancer: PubMed, EMBASE, CINAHL, AltHealthWatch, the Cochrane Library, and the National Library of Science and Technology, from inception to the end of October 2009. The PubMed search was updated to the end of August 2014. We used a broad-based MeSH and keyword approach combining clinical (lung cancer) and therapeutic (PSK) search terms. We hand searched bibliographies of review articles for additional references. Separate searches were conducted independently by the first and second authors (HF and DAK). Table 1 provides details on the search terms and strategy used to collect the records for screening from both searches employed. Figure 1 provides a flowchart of the searches.
Table 1. Search Strategy. Search Strings PSK OR polysaccharide K OR Krestin OR polysaccharide K* OR polysaccharopeptide OR PSP OR Coriolus versicolor
AND Lung Neoplasma OR Chemoprevention
a
“Lung neoplasm” was the MeSH term used in PubMed; in other databases, “Lung cancer” was used.
We piloted data extraction forms in duplicate to assess inter-researcher reliability. On completion of data extraction in duplicate for fifty percent of human level studies, there were no major inconsistencies, and further duplication of data extraction was found to be redundant. Extraction sheets were prepared partly based on the Consolidated Standards of Reporting Trials (CONSORT) statement,9,10 the NewcastleOttawa scale (NOS),11 and the Score for Assessment of Physical Experiments on Homeopathy (SAPEH)12 for human trials, observational studies, and preclinical studies, respectively. For randomized controlled trials, quality assessment was performed according to the Jadad scoring system.13 Screening of studies was initially conducted based on title review. In the event of uncertainty, abstracts and/or full texts were also reviewed. English language publications were included for all levels of evidence. Since the majority of human studies for PSK have been conducted in Japan, Japanese language publications were included if they reported controlled human trials; data for these was extracted by the third author (MI). Human trials had to assess the efficacy of PSK or other C versicolor preparations in lung cancer for the purposes of treatment, primary or secondary prevention, reduction of side effects and toxicities associated with chemotherapy or radiation therapy, or assessment of potential interactions with these therapies. All types of lung cancers (small cell lung cancer, non–small cell lung cancer, mesothelioma) were included. For inclusion, preclinical studies had to be conducted in lung cancer models and examine either PSK or other C versicolor preparations for their anticancer effects or their interaction with conventional chemo- or radiation- therapy. Preclinical studies were categorized by results as positive, negative, neutral, or mixed. The term positive designates studies that found significant anticancer effects from PSK in models of lung cancer, alone or additively with other agents; negative designates studies that found significant procarcinogenic effects alone or in combination with other agents; and neutral designates studies that found neither significant beneficial effect nor any evidence of harm. In the absence of reported levels of significance, the authors’ interpretation was used to guide classification.
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Fritz et al
214 records selected for initial screening for efficacy in Lung Cancer articles
167 records excluded after deduplication and initial title/ abstract review
47 full text articles screened
16 records excluded - 3 Reviews - 13 Not relevant to PSK and lung cancer, not related to treatment effects, non-English preclinical studies, or a duplication of data
31 Articles included for Data Extraction and Analysis - 15 Reports of 11 controlled human trials - 7 reports of 6 RCTs - 8 reports of 5 non-randomized controlled trials - 0 Observational Studies - 17 Preclinical studies (1 included in RCT report)
Figure 1. Literature flowchart.
Results The combined searches provided 214 records for screening. Fifteen reports of 11 controlled human trials14-28 and 17 preclinical studies29-44 were included in the efficacy analysis. One randomized controlled trial article also included the report of an animal study, for a total of 31 articles. Nine of the 15 reports were Japanese language publications.18-20,22-27 Figure 1 shows a flowchart of the literature search and study selection.
Preclinical Evidence Of the 17 included preclinical studies, 15 supported the anticancer effects of PSK. Two studies showed no significant effects and no studies found harmful or negative effects. Seven of the 17 supported immune mediated antitumor activity including tumor cell lysis by NK and LAK cells; seven supported antimetastatic activity; six supported anticancer effects in vivo by decreasing tumor size or incidence of cancer after carcinogen exposure; five supported the ability of PSK to increase survival in vivo; two studies supported antiproliferative effects; one study supported
proapoptotic effects; and five supported general improvement in immune function by way of increased cell counts and cytokine levels as well as preventing chemotherapyinduced immune suppression. There was no evidence of PSK having a procarcinogenic effect. Table 2 summarizes the preclinical evidence.21,29-44 Immunologic Activity and Chemotherapy-Induced Immune Suppression. In vivo administration of PSK was able to abolish the decrease in phagoctyic activity and the number of Kupffer cells otherwise induced by the chemotherapeutic agents 1-2-tetrahydrofuryl-5-fluorouracil (FT) and 5-fluorouracil (5-FU).41 In other lung cancer models, PSK increased the concentrations of lymphocytes, macrophages, and neutrophils in bronchoalveolar lavage fluid and induced synthesis of TNF-α, IL-1α, IL-6, MIP-1α, and MIP-1β31; normalized splenic NK activity33; and increased the numbers of CD8+ CD4− T cells and CD4+ CD8− T cells in the thymus.39 Immune-Mediated Antitumor Activity. Ishihara et al,32,33 Ueno et al,42 and Vanky et al,44 found that PSK increased the antitumor cytotoxicity of various immune cells, including neutrophils, NK cells, and lymphocytes. PSK increased neutrophil mediated cytotoxicity and increased NK cell mediated lysis of tumor cells, prolonging survival and decreasing metastasis32,33 and increased the antitumor activity of splenic LAK cells and tumor infiltrating lymphocyte (TIL) cells.42 In vitro, PSK at clinically attainable levels augmented the cytotoxicity of NK cells and large granular lymphocytes (LGLs) taken from lung cancer patients against various cancer cells.37 Similar effects were found when using lymphocytes and target cancer cells taken from untreated lung (and other) cancer patients.36 In animals, PSK administered within 48 hours of birth was found to significantly increase mean survival time up to 189% when animals were subsequently transplanted with lung cancer cells (P < .001); CD8+ T cells were thought to be the effector cells since blockade of CD8+ cell activity inhibited this effect.39 Nonspecific Antitumor Effect. Ito et al34 found that PSK reduced tumor growth in vivo, but mechanisms were not examined. Katoh and Ooshiro38 found that PSK alone in high doses was able to inhibit lung tumor growth, but there was no additive effect in combination with uracil/tegafur/ leucovorin chemotherapy. Metastasis. Ishihara et al31 found that PSK given to a model of lung metastasis significantly reduced the number of lung nodules (P < .001) and increased the cytostatic activity of bronchoalveolar cells (P < .05) compared with controls. Further studies by the same team found similar effects, as well as reduced weight loss in the treated animals.32,33 Matsunaga et al40 found that PSK significantly reduced the
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Integrative Cancer Therapies
number of metastases and increased survival time compared with control animals (P < .05) through inhibition of tumor cell adhesion to membrane, degradation of collagen IV, chemotaxis of tumor cells, and haptotaxis to fibronectin.40 In splenectomized animals treated with FT and 5-FU chemotherapy, PSK was able to offset the metastasis promoting effects of these drugs.41 In combination with chemotherapy, PSK augmented the effect of cyclophosphamide and IL-2, suppressing lung metastasis, and increasing survival.42 Following thoracic surgery, PSK nonsignificantly improved survival and decreased lung metastasis.29,30 When administered postoperatively with both surgical tumor removal and cyclophosphamide chemotherapy, PSK reduced lung metastasis compared with either cyclophosphamide or PSK alone.43 Proliferation and Apoptosis. PSK significantly (P < .001) reduced proliferation of A549 lung cancer cells up to 80%; produced cell cycle arrest; increased the percentage of apoptotic cells in part by increasing expression of capsase 3; and increased peripheral blood lymphocyte (PBL) proliferation 4.5-fold over control (P < .01) when combined with IL-2.35
Nonrandomized Controlled Trials There were eight reports of five nonrandomized controlled trials for the treatment of lung cancer.16-18,22,23,25-27 This category includes studies for which no randomization was reported as well as studies that explicitly stated that randomization was not used. Often the treating physician’s clinical judgment as to which treatment would most benefit the particular patient was the deciding factor when choosing between several treatments, including chemotherapy alone, chemotherapy and PSK, chemotherapy and OK-432 (a bacterial-derived immunotherapy), or chemotherapy and both PSK and OK-432. In three of the five trials, PSK plus chemotherapy and/or radiation was compared with chemotherapy and/or radiation alone. In two trials, PSK was given without concurrent chemotherapy, and in one of these, PSK was given to stages I to III patients who had responded to previous radiation therapy.16,17 Median Survival. All five studies used measures of survival as endpoints. Significantly increased median survival was reported with use of PSK among stage 0 to 1 non–small cell lung cancer patients who had responded to radiation 16, 17 ; in patients receiving PSK, OK-432, or both as immunotherapy in addition to chemotherapy or radiation therapy.23 One study found no difference between treatment with immunotherapy (PSK, OK-432, or Tegafur) plus chemotherapy compared to chemotherapy alone,22 and one study reported increased median survival associated with use of PSK but did not provide a measure of significance for the finding.18
One-,Two-, and Five-Year Survival. One study reported significantly increased 5-year survival in patients receiving PSK following radiotherapy compared with no adjunctive therapy, 30% compared with 9% (P < .001), and two studies failed to report significance. Other studies reported no significant effect for PSK alone, but significantly increased 1-year survival associated with combined use of both PSK and OK-432 compared with no adjunctive therapy (P < .025).18 Ogawa et al25-27 and Kawamura et al22 reported increased survival at 1 and 2 years associated with use of either PSK or OK-432, or both, but did not report significance. Hayakawa et al16,17 found that use of PSK among patients with stage III disease increased their 2-year survival such that it was superior to that of stages I and II patients who received chemotherapy without PSK, 43% versus 26%, respectively (P < .05).
Randomized Controlled Trials There were seven reports of six randomized controlled trials of PSK or PSP for the treatment of lung cancer.14,15,19-21,24,28 All the randomized controlled trials involved administration of 3 g/d of PSK or PSP alongside standard chemotherapy, with the exception of the study by Tsang et al28 during which PSP was given for 28 days following chemotherapy. All six studies showed benefit on at least one of the following endpoints: parameters of immune function, body weight, performance score, tumor-related symptoms, or survival. Tables 3 and 4 provide a description of the design and outcomes of the included studies.14-28 Immune Function. PSK was found to shorten the duration of bone marrow suppression associated with chemotherapy,20,21 and beneficially increased white blood cell counts,15,21,28 hemoglobin,15 platelets,21 neutrophils,28 IgG and IgM,28 NK cell activity,14 IL-1,14 IL-2,15 and CD4/CD8 ratio and/or CD4 counts.14,15 Two of 3 studies found that PSP significantly increased or stabilized body weight compared with control patients receiving chemotherapy alone.14,15,28 Performance Status and Body Weight. Two of three studies found that PSP or PSK was able to significantly improve performance status.14,15,24 One study found no significant effect on tumor response rates or tumor-associated symptoms, but found that the PSK group had significantly fewer study withdrawals due to progressive disease, 5.9% compared with 23.5% in the control group (OR = 4.9, 95% CI = 1.0-25.5, P = .04).28 Cancer-Associated Symptoms. Two of three studies found significant patient-reported improvements in tumor-related symptoms including fatigue, loss of appetite, nausea and vomiting, dry mouth and throat, spontaneous or night
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5
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y
Kariya et al36
5
—
11
y
y
y
y
—
y
—
—
y
y
y
y
y
y
y
y
—
41
30 in LuCa arm
52
41
—
8 per group
—
—
NR
NR
30
18
60
56
120 in LuCa arm
45 in LuCa arm
—
n
CY
—
OK-432
—
MMC; IFN, IL-2
5-FU FT
IFN, IL-2
—
CY w/w/o IL-2
—
Carboplatin, etoposide
—
—
—
—
UFT/LV
—
6
—
y
—
—
—
—
—
—
—
y
y
y
—
—
y
y (PSK alone)
—
5
—
—
NS
—
—
—
—
—
y
y
y
y
—
—
y
n
—
2
—
—
—
—
—
—
—
—
—
n
y
—
—
—
—
—
y
1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
y
7
y (w chemo)
—
—
n
—
y (w chemo)
—
—
y
y
—
y
y
y
—
—
—
7
—
—
—
—
y
y
y
y
y
—
—
y
—
y
—
—
—
5
—
—
—
—
—
y
—
y
—
—
y
y
y
—
y
—
—
Anticancer Immune-Mediated Effect Effect on Immune ↑Survival/ Effect (↓Lung ↓Mortality/ System Apart From Antiproliferative Antimetastatic/ on Tumor (↑ Tumor Tumor Incidence/ ↑Time to Tumor Effect/Growth Proapoptotic Angiogenic/ Cell Lysis/Cytotoxicity Effect on Tumor Chemotherapy Multiplicity/Volume) Development by Immune Cells) (↑ No. Immune Cells) Inhibition Effect Invasive Effecta
Outcomes Measured and Effects
↑ NK lytic activity
PSK + CY following surgical removal of primary tumor markedly ↓ lung colony formation compared to either agent alone
—
Nonsignificant tendency to ↑survival with PSK
NS ↓ in lung mets
MMC did not abrogate the effect of PSK; IFN augmented effect of PSK in certain LΦ subsets; IL-2 had no effect on PSK’s action
PSK abolished the ↓in phagocytic activity, number of Kupffer cells, and thymus weight cz’d by 5-FU and FT
PSK augments NK cell cytotoxicity independently of IFN and IL-2
—
PSK augmented effect of CY
↓ Chemotaxis, adhesion to membrane, and degradation of collagen IV
Significantly better effect when PSK combined w chemo c/t chemo alone
↑ TNF-α, superoxide ions in NΦ
↑ TNF-α, IL-1α, IL-6, MIP1α, β; ↑ LΦ, MΦ, NΦ
—
PSK alone ↓ tumor volume, but no additive effect w UFT/LV
—
Note
15 + 2n 0–
+
+
n
n
+
+
+
+
+
+
+
+
+
+
+
+
+
+ /−/ n / m
Abbreviations: 5-FU, 5 fluorouracil; CY, cyclophosphamide; FT, a derivative of 5-fluorouracil; IFN, interferon; IL-2, interleukin 2; LΦ, lymphocyte; LV, leucuovorin; MΦ, macrophages; MMC, mitomycin C; NΦ, neutrophils; NK, natural killer cells; OK-432, a bacterial-based immunotherapy used commonly in Japan; UFT, tegafur/uracil; w/w/o with or without. “+” results in favor of PSK; “−” detrimental results found with PSK use; “n” no significant effect or neutral result; “y” yes effect demonstrated; — not applicable/outcome not assessed. a Includes effects on tumor growth observed in animal models of metastasis to the lungs, such as that induced by intravenous or subcutaneous injection of lung cancer cells, as well as results from in vitro on markers such as vascular endothelial growth factor or invasive capacity. Thus, results from animal models of metastasis are differentiated from effects on primary tumor growth induced by administration of carcinogen, and are detailed under this column, whereas measures of (nonmetastatic) primary tumor growth are categorized under “Anticancer Effect.”
Total
Usui et al
43
—
—
Tsuru et al41
Ito et al34
y
Kariya et al37
—
y
Vanky et al44
—
—
Ueno et al42
Hattori et al29
y
Matsunaga et al40
Hattori et al30
—
—
Ishihara et al32
Katoh21
—
—
Ishihara et al33
Ishihara et al31
—
Matsunaga et al39
y
In Vitro In Vivo
—
35
Katoh et al38
Jiménez-Medina et al
Reference
Design
Table 2. Preclinical Evidence.
6
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Age, y
NR
M 351 F 134
NR
NR
Liu et al (1999)15
Liu et al (1993)14
M 89 F 18
NR
Range 33 to 88
NR
Matsushima et al (1980)23
Ogawa et al (1981, 1982a, 1982b)25-27
NR
NR
NR
PS
NR
KPS 100 to 50
PS 0-3
PS 0-2
NR
Stage III and IV SCLC and NSCLC
NR
Most stage III or IV, NSCLC NR
Stage III or IV SCLC or NSCLC
Stage I-IV
Stage I-III NSCLC patients who responded to radiation therapy
Stage III and IV NSCLC (adenocarcinoma)
Stage I-IV NSCLC
PSK 3 g/d with or w/o rG-CSF 75 µg/d plus carboplatin + etoposide chemotherapy (mean 4.7 cycles) PSP 3g/d ×2 mo plus standard chemotherapy or radiotherapy according to cancer type PSP 3060 mg/d + shark liver extract 450 mg/d ×2 mo plus chemotherapy according to cancer type
PSP 3060mg/d following six 3-wk cycles of paclitaxol + carboplatin
Intervention
NR
NR
NR
NR
Radiation therapy
Patients received one or more of the following in combination: 1. PSK 3 g/d 2. OK-432 5 KE 2×/wk 3. Tegafur 600 mg/d All group could also receive chemo and radiation therapy 1. PSK 3 g/d ×3 d/wk (cycles) 2. OK-432 bacterial immunotherapy 2.0 KE/d IM 3 d/wk 3. Both PSK and OK-432 1. PSK 3 g/d 2. OK-432, dose NR Both with chemo or radiation therapy 3. PSK plus OK-432 + chemo/radiation therapy 1. PSK dose NR 2. OK-432 dose NR 3. Both concurrently with chemo and radiation therapy
PSK 3 g/d as intermittent dosing: 2 wk on, 2 wk off
Surgical removal 1. PSK 3 g/d starting 2 wk after surgery of lung cancer + chemotherapy with one of several regimens as determined by the clinician (VCR, MMC, MTX, EX, 5-FU) 2. OK-432 1-2 to 5 KE 2 d/wk every 2 wk No previous PSK 3 g/d plus vindesine/cisplatin therapy chemotherapy
Karnofsy Chemo, PS ~86 radiation, (mean) and/or surgery in most Stage II-IV SCLC or PS 0-3 Lobectomy in NSCLC most, radiation in some Esophageal cancer, n = 223 NR NR Stomach cancer, n = 230 Lung cancer, n = 197 Stage I to IV: KPS ≥ 60 NR Esophageal cancer, n = 162 Stomach cancer, n = 152 Lung cancer, n = 171
Stage III or IV inoperable NSCLC
Staging
Previous Chemo or Surgery
“Long term” until progression or death
NR
2y
2 mo
2 mo
NR
28 d
NR
2-4 y depending on disease progression
Chemo and “As long as radiation possible” only (no immunotherapy)
Chemo or radiation therapy only (no immunotherapy)
No treatment
Chemo and Up to 32 mo radiation therapy only
No adjuvant therapy
Chemotherapy only
Chemotherapy only
placebo + chemo or radiation therapy Placebo + chemotherapy
Carboplatin + etoposide only
paclitaxol + carboplatin only
Control
Treatment Duration
NR
Enrollment: 19992001 follow-up:
172
107
172
38
188
138
113
At least 5 years between Jan 1975 and December 1979
NR
5y
1979-1988: 9 y
Enrollment: 19761989 (13y) follow-up: till December 1994
June 1986 to May 1989: 3 y
July 1979to December 1982: 3.5 y
650 April 1996 to (197 lung) September 1997: 18 mo 485 February to July (171 lung) 1992: 6 mo
14
68
Sample Size Study Duration
n
n
n
n
n
n
n
y
y
n
NR
n
n
n
n
n
y
y
y
y
y
y
n
n
n
n
n
y
n
n
n
n
y
—
—
—
—
—
3
1
3
1
1
5
Dropout JADAD Score /LTFU Blinding Random Reported (RCTs)
Abbreviations: CA, cancer; CAD, coronary artery disease; comb, combination; f/u, follow-up; GI, gastrointestinal; LTFU, loss to follow-up; NR, not reported; NSCLC, non–small cell lung cancer; pop, population; PS, performance score; SCLC, small cell lung cancer; w, with.
M 142 F 30
NR
NR
M 124 F 18
M 31 F7
NR
NR
NR
NR
NR
NR
M 93 F 45
Median 60 Hiyoshi et al (1981) (range 3018 80+) Nippon
Japanese language Kawamura Range 40-89 et al (1990)22
NR Nishiwaki et al (1990)24 Nonrandomized trials English language Hayakawa et Over half of patients al (1993, ≥70 1997)16,17
Japanese language 70 M 79, F 34 Ikeda et al (1986)19
M 11, F 3
Mean 59
M 132, F 480
Gender
Katoh et al (1998)20,21
Randomizd controlled trials English language Tsang et al T group 61; C group 55 (2003)28 (mean)
Reference
Smokers/ Asbestos Exposure
Population
Table 3. Methodologies of Human Trials.
7
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—
—
—
—
Tsang et al (2003)28
Katoh et al (1998)21,22
Liu et al (1999)15
Liu et al (1993)14
Stage IV group, Months
—
—
—
—
OK432 12.2; Both 14.4; Control 7.5 PSK 7.6 OK432 7.0; Both 5.0; Control 3.3 Immunotherapy No 8.3 mo immunotherapy 3.8 mo — —
PSK 9.0
OK-432 28; Tegafur 19
PSK 19
—
13.5 12
—
300 d 457 d 265 d
30 15.5
301 d 576 d 255 d
—
—
—
—
—
P < .05
NR
NR
NR
P < .001 P = 0.38
—
NS P =.075 NS
P < .01
P < .01
NR
—
—
—
—
P Value
Measure
T
—
—
—
—
—
—
—
—
—
—
—
PSK 11 CR 12 PR 0 PD 4 DS —
—
—
9.5 (all no PSK) 14/93 34/93 45/93
Other
—
—
C 0 CR 0 PR 5 PD 20 DS
—
—
—
—
—
—
—
—
—
—
Control 18 CR 13 PR 0 PD 16 DS —
No./total: 31/135 52/139 58/135 60/139 46/135 27/139
20.5 (all PSK) No. / total: 38/95 26/95 31/95
0 CR O PR 4 PD 25 DS
—
—
—
Tumor response
Change in body weight: ↑≥1 kg Stable ↓≥1 kg
Time to recurrence (mo) Change in body weight: ↑ Stable ↓
Tumor response
Other T
C
—
—
—
—
—
—
—
—
—
—
—
NR
—
—
—
—
—
—
—
—
All Stage3 Stage4
—
—
—
45
—
—
—
—
P Value
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
16.9% 17.9% P = 1.00 37.5% 11.1% P = .046 6.4% 22.5% P = .058
—
—
—
Effectivenessa
85.5
—
—
Measure
—
Respiratory Pain Fatigue Weight loss —
No change c/t/b
T
Stage 4
Stage 3
—
Stage IV patients
Stage III patients
All patients
—
—
26%
OK-432 100%; Control 85.7% OK-432 68.4%;Control 44.5% —
OK-432 82.1%; Control 61.8%
—
P Value
Measure
4-y survival all patients
—
NR
—
SCC patients: Stage 0-1 Stage 2-3
5-y survival All patients
—
P < .10 trend Stage I c/t in active control P < .01 Stage III
NR
17.8%
PSK, OK-432 or Both: 48.4%
—
PSK 15.4%
5.6%
None 25%
—
OK-432 16.7%; Both 25.0%; Control 5.6%
NR
NR
NR
—
Sign improvement c/t/b
T ↓WBC+ neutrophils c/t/b
—
—
Survival at 65 mo (5.5y)
—
—
17% 4%
9%
OK-432 NR; Control 61.2% OK-432 35.0%; Control11.1% —
OK-432 36.7% Control 34.7%
4- or 5-y Survival
—
7/52
—
—
—
1/55
—
—
—
P Value
Measure
NR
—
—
—
—
P < .05 P < .005
P < .001
—
P < .1 trend c/t in active control P < .01 c/t in active control
NR
T
KPS: ↑ Stable ↓
—
—
—
—
—
—
—
—
—
Score 0 1 to 2
—
—
—
7/93 65/93 21/93
—
P < .05
P=.04 OR 4.9 95%CI 1.025.5 —
P Value
—
—
—
—
—
—
—
—
N = 15 56
—
—
—
—
—
—
—
—
—
—
—
N= 9 58
—
—
—
Performance Score
—
—
—
—
—
—
—
—
P = .333
—
—
—
No./total: 40/135 P = .0031 62/139 81/135 72/139 14/135 5/139
No. / total: 12/96 79/96 5/96
—
23.5%
C
Performance Score
Withdrawals 5.9% d/t DP
P < .001 for KPS: both, P < .05 ↑≥10 Stable ↓>10
P < .01 for all
“Tendency”
p
