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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 tumor-related 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 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, 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	AND
PSK OR	Lung Neoplasm^a OR
polysaccharide K OR	Chemoprevention
Krestin OR
polysaccharide K* OR
polysaccharopeptide OR
PSP OR
Coriolus versicolor

“Lung neoplasm” was the MeSH term used in PubMed; in other databases, “Lung cancer” was used.

Figure 1.

Literature flowchart.

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 Newcastle-Ottawa 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.

Results

The combined searches provided 214 records for screening. Fifteen reports of 11 controlled human trials^14-28 and 17 preclinical studies^29-44 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 chemotherapy-induced immune suppression. There was no evidence of PSK having a procarcinogenic effect. Table 2 summarizes the preclinical evidence.^21,29-44

Table 2.

Preclinical Evidence.

Design					Outcomes Measured and Effects
Reference	In Vitro	In Vivo	n	Chemotherapy	Anticancer Effect (↓Lung Tumor Incidence/Multiplicity/Volume)	↑Survival/↓Mortality/↑Time to Tumor Development	Antiproliferative Effect/Growth Inhibition	Proapoptotic Effect	Antimetastatic/Angiogenic/Invasive Effect^a	Immune-Mediated Effect on Tumor (↑ Tumor Cell Lysis/Cytotoxicity by Immune Cells)	Effect on Immune System Apart From Effect on Tumor(↑ No. Immune Cells)	Note	+ /−/ n / m
Jiménez-Medina et al³⁵	y	—	—	—	—	—	y	y	—	—	—	—	+
Katoh et al³⁸	—	y	45 in LuCa arm	UFT/LV	y(PSK alone)	n	—	—	—	—	—	PSK alone ↓ tumor volume, but no additive effect w UFT/LV	+
Matsunaga et al³⁹	—	y	120 in LuCa arm	—	y	y	—	—	—	—	y	—	+
Ishihara et al³³	—	y	56	—	—	—	—	—	y	y	—	↑ NK lytic activity	+
Ishihara et al³¹	—	y	60	—	—	—	—	—	y	—	y	↑ TNF-α, IL-1α, IL-6, MIP1α, β;↑ LΦ, MΦ, NΦ	+
Ishihara et al³²	—	y	18	—	y	y	—	—	y	y	y	↑ TNF-α, superoxide ions in NΦ	+
Katoh²¹	—	y	30	Carboplatin, etoposide	y	y	y	—	—	—	y	Significantly better effect when PSK combined w chemo c/t chemo alone	+
Matsunaga et al⁴⁰	y	y	NR	—	y	y	n	—	y	—	—	↓ Chemotaxis, adhesion to membrane, and degradation of collagen IV	+
Ueno et al⁴²	—	y	NR	CY w/w/o IL-2	—	y	—	—	y	y	—	PSK augmented effect of CY	+
Vanky et al⁴⁴	y	—	—	—	—	—	—	—	—	y	y	—	+
Kariya et al³⁷	y	—	—	IFN, IL-2	—	—	—	—	—	y	—	PSK augments NK cell cytotoxicity independently of IFN and IL-2	+
Tsuru et al⁴¹	—	y	8 per group	5-FUFT	—	—	—	—	y (w chemo)	y	y	PSK abolished the ↓in phagocytic activity, number of Kupffer cells, and thymus weight cz’d by 5-FU and FT	+
Kariya et al³⁶	y	—	—	MMC;IFN, IL-2	—	—	—	—	—	y	—	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	+
Hattori et al²⁹	—	y	41	—	—	—	—	—	n	—	—	NS ↓ in lung mets	n
Hattori et al³⁰	—	y	52	OK-432	—	NS	—	—	—	—	—	Nonsignificant tendency to ↑survival with PSK	n
Ito et al³⁴	—	y	30 in LuCa arm	—	y	—	—	—	—	—	—	—	+
Usui et al⁴³	—	y	41	CY	—	—	—	—	y (w chemo)	—	—	PSK + CY following surgical removal of primary tumor markedly ↓ lung colony formation compared to either agent alone	+
Total	5	11			6	5	2	1	7	7	5		15 +2 n0 –

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.

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.”

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 metastasis^32,33 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 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 al^25-27 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 al^16,17 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

Table 3.

Methodologies of Human Trials.

Reference	Population						Intervention	Control	Treatment Duration	Sample Size	Study Duration	Blinding	Random	Dropout /LTFU Reported	JADAD Score (RCTs)
Reference	Age, y	Gender	Smokers/Asbestos Exposure	Staging	PS	Previous Chemo or Surgery	Intervention	Control	Treatment Duration	Sample Size	Study Duration	Blinding	Random	Dropout /LTFU Reported	JADAD Score (RCTs)
Randomizd controlled trials
English language
Tsang et al (2003)²⁸	T group 61; C group 55(mean)	M 132,F 480	NR	Stage III or IV inoperable NSCLC	Karnofsy PS ~86 (mean)	Chemo, radiation, and/or surgery in most	PSP 3060mg/dfollowing six 3-wk cycles of paclitaxol + carboplatin	paclitaxol + carboplatin only	28 d	68	Enrollment: 1999-2001follow-up:	NR	y	y	5
Katoh et al (1998)^20,21	Mean 59	M 11, F 3	NR	Stage II-IV SCLC or NSCLC	PS 0-3	Lobectomy in most, radiation in some	PSK 3 g/d with or w/o rG-CSF 75 µg/dplus carboplatin + etoposide chemotherapy (mean 4.7 cycles)	Carboplatin + etoposide only	NR	14	NR	n	y	n	1
Liu et al (1999)¹⁵	NR	NR	NR	Esophageal cancer, n = 223Stomach cancer, n = 230Lung cancer, n = 197	NR	NR	PSP 3g/d ×2 moplus standard chemotherapy or radiotherapy according to cancer type	placebo + chemo or radiation therapy	2 mo	650(197 lung)	April 1996 to September 1997: 18 mo	y	y	n	1
Liu et al (1993)¹⁴	NR	M 351F 134	NR	Stage I to IV:Esophageal cancer, n = 162Stomach cancer, n = 152Lung cancer, n = 171	KPS ≥ 60	NR	PSP 3060 mg/d + shark liver extract 450 mg/d ×2 moplus chemotherapy according to cancer type	Placebo + chemotherapy	2 mo	485(171 lung)	February to July 1992: 6 mo	y	y	n	3
Japanese language
Ikeda et al (1986)¹⁹	<49 to >70	M 79, F 34	NR	Stage I-IV NSCLC	NR	Surgical removal of lung cancer	1. PSK 3 g/d starting 2 wk after surgery + 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	Chemotherapy only	2 y	113	July 1979to December 1982: 3.5 y	n	y	n	1
Nishiwaki et al (1990)²⁴	NR	M 93F 45	NR	Stage III and IV NSCLC (adenocarcinoma)	PS 0-2	No previous therapy	PSK 3 g/d plus vindesine/cisplatin chemotherapy	Chemotherapy only	NR	138	June 1986 to May 1989: 3 y	n	y	y	3
Nonrandomized trials
English language
Hayakawa et al (1993, 1997)^16,17	Over half of patients ≥70	M 124F 18	NR	Stage I-III NSCLC patients who responded to radiation therapy	PS 0-3	Radiation therapy	PSK 3 g/d as intermittent dosing: 2 wk on, 2 wk off	No adjuvant therapy	“Long term” until progression or death	188	Enrollment: 1976-1989 (13y)follow-up: till December 1994	n	n	n	—
Japanese language
Kawamura et al (1990)²²	Range 40-89	M 31F 7	NR	Stage I-IV	KPS 100 to 50	NR	Patients received one or more of the following in combination:1. PSK 3 g/d2. OK-432 5 KE 2×/wk3. Tegafur 600 mg/dAll group could also receive chemo and radiation therapy	Chemo and radiation therapy only	Up to 32 mo	38	1979-1988: 9 y	n	n	n	—
Hiyoshi et al (1981) Nippon¹⁸	Median 60 (range 30-80+)	M 142F 30	NR	Stage III or IV SCLC or NSCLC	NR	NR	1. PSK 3 g/d ×3 d/wk (cycles)2. OK-432 bacterial immunotherapy 2.0 KE/d IM 3 d/wk3. Both PSK and OK-432	No treatment	2-4 y depending on disease progression	172	5 y	n	n	n	—
Matsushima et al (1980)²³	Range 33 to 88	M 89F 18	NR	Most stage III or IV, NSCLC	NR	NR	1. PSK 3 g/d2. OK-432, dose NRBoth with chemo or radiation therapy3. PSK plus OK-432 + chemo/radiation therapy	Chemo or radiation therapy only (no immunotherapy)	NR	107	NR	n	n	n	—
Ogawa et al (1981, 1982a, 1982b)^25-27	NR	NR	NR	Stage III and IV SCLC and NSCLC	NR	NR	1. PSK dose NR2. OK-432 dose NR3. Both concurrently with chemo and radiation therapy	Chemo and radiation only (no immunotherapy)	“As long as possible”	172	At least 5 years between Jan 1975 and December 1979	n	n	n	—

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.

Table 4.

Outcomes of Human Trials.

Reference	Median Survival				Other				Effectiveness^a				Tumor-Related Symptoms				Immunological Parameters				Performance Score
RCTs English	Measure	T	C	P Value	Measure	T	C	P Value	Measure	T	C	P Value	Measure	T	C	P Value	Measure	T	C	P Value	Measure	T	C	P Value
Tsang et al (2003)²⁸	—	—	—	—	Tumor response	0 CRO PR4 PD25 DS	0 CR0 PR5 PD20 DS	NR	—	—	—	—	RespiratoryPainFatigueWeight loss	No change c/t/b	NR	NS	WBC, neutrophils, serum IgG/IgM	Sign improvement c/t/b	↓WBC+ neutrophils c/t/b	p<0.05	Withdrawals d/t DP	5.9%	23.5%	P=.04OR 4.995%CI 1.0-25.5
Katoh et al (1998)^21,22	—	—	—	—	Time to recurrence (mo)	20.5(allPSK)	9.5(all no PSK)	—	—	—	—	—	—	—	—	—	WBC, platelets	Reduced post chemo ↓WBCplatelets	NR	“Tendency”	—	—	—	—
Liu et al (1999)¹⁵	—	—	—	—	Change in body weight:↑Stable↓	No. /total:38/9526/9531/95	14/9334/9345/93	P < .05	Percent	85.5	45	P < .001	No. who improved inFatigueAppetiteAnorexia and vomitingPain	Of 96 patients78692425	Of 93 patients47311920	P < .01P < .01P < .05P < .05	↑WBC+ Hgb,less ↓ CD4/CD8 ratio	Change sign b/w/g	—	P < .01 for all	KPS:↑Stable↓	No. / total:12/9679/965/96	7/9365/9321/93	P < .05
Liu et al (1993)¹⁴	—	—	—	—	Change in body weight:↑≥1 kgStable↓≥1 kg	No./total:52/13960/13927/139	31/13558/13546/135	P = .0041	Percent	82.02(114 of 139 pt)	45.16(61 of 135 pt)	P < .001	No. who improved inFatigueAppetiteNVPainPalpitation SOB	No./total90/12587/11430/4443/6741/75	No./total42/10737/10615/3123/6926/69	P = .05 for all	↑NK activity, IL-1, CD4 counts	Change sign b/w/g	—	P < .001 for both, P < .05	KPS:↑≥10Stable↓>10	No./total:62/13972/1395/139	40/13581/13514/135	P = .0031

RCTs Japanese	Median Survival				Other				Effectiveness^a				1- or 2-y Survival				4- or 5-y Survival				Performance Score

Ikeda et al (1986)¹⁹	All patients	PSK1.85 y	OK-4321.27 y;Control1.02 y	NR	Tumor response	PSK11 CR12 PR0 PD4 DS	Control18 CR13 PR0 PD16 DS	NR	—	—	—	—	1-y survival all patients	PSK 88.9%	OK-432 82.1%;Control61.8%	NR	4-y survival all patients	PSK55.9%	OK-432 36.7%Control34.7%	NR	—	—	—	—
	Stage I patients	Longer survival c/t OK or control	NR	P < .01	—	—	—	—	—	—	—	—	Stage I	PSK100%	OK-432 100%;Control85.7%	P < .10 trend c/t in active control	Stage I	PSK87.5%NR	OK-432 NR;Control61.2%	P < .1trend c/t in active control	—	—	—	—
	Stage III patients	Longer survival c/t control	NR	P < .01	—	—	—	—	—	—	—	—	Stage III	PSK 91.7%	OK-43268.4%;Control 44.5%	P < .01	Stage III	PSK39.0%	OK-43235.0%;Control11.1%	P < .01 c/t in active control	—	—	—	—
Nishiwaki et al (1990)²⁴	AllStage IIIStage IV	301 d576 d255 d	300 d457 d265 d	NSP =.075NS	—	—	—	—	AllStage3Stage4	16.9%37.5%6.4%	17.9%11.1%22.5%	P = 1.00P = .046P = .058	—	—	—	—	—	—	—	—	Score01 to 2	N = 1556	N= 958	P = .333
Nonrandomized trials
English
Hayakawa et al (1993, 1997)^16,17,b	—	—	—	—	—	—	—	—	—	—	—	—	2-year survivalAll patients	57%	26%	NR	5-y survivalAll patients	30%	9%	P < .001	—	—	—	—
	SCC patients:Stage 0-1Stage 2-3	3015.5	13.512	P < .001P = 0.38	—	—	—	—	—	—	—	—	—	—	—	—	SCC patients:Stage 0-1Stage 2-3	36%17%	17%4%	P < .05P < .005	—	—	—	—
Japanese
Kawamura (1990)²²	Days	PSK19	OK-432 28;Tegafur 19	NR	—	—	—	—	—	—	—	—	All patients	Immunotherapy68.4%	No immunotherapy51.1%	NR	5-y survival	Immunotherapy3.4%	No immunotherapy7.0%	NR	—	—	—	—
Hiyoshi et al (1981)¹⁸	Stage III group,Months	PSK 9.0	OK432 12.2;Both 14.4;Control7.5	NR		—	—	—	—	—	—	—	Stage III patients	PSK 34.8%	OK-432 51.9%;Both 66.7%;Control 25%	PSK alone NS;Both p<0.025c/t control	—	—	—	—	—	—	—	—
	Stage IV group,Months	PSK 7.6	OK432 7.0;Both 5.0;Control3.3	NR		—	—	—	—	—	—	—	Stage IV patients	PSK 15.4%	OK-432 16.7%;Both 25.0%;Control 5.6%	NR	—	—	—	—	—	—	—	—
Matsushima et al (1980)²³	Months	Immunotherapy 8.3 mo	No immunotherapy 3.8 mo	P < .05		—	—	—	—	—	—	—	—	—	—	—	Survival at 65 mo (5.5y)	7/52	1/55	NR	—	—	—	—
Ogawa et al (1981, 1982a, 1982b)^25-27	—	—	—	—	—	—	—	—	—	—	—	—	Stage 3	PSK, OK-432 or Both:48.4%	None25%	NR	—	—	—	—	—	—	—	—
	—	—	—	—	—	—	—	—	—	—	—	—	Stage 4	17.8%	5.6%	NR	—	—	—	—	—	—	—	—

Abbreviations: CR, complete response; c/t, compared to; c/t/b, compared to baseline; DP, disease progression; DS, disease stabilization; d/t, due to; mo, months; NR, not reported; NS, not significant; NV, nausea and vomiting; PD, progressive disease; PR, partial response; SCC squamous cell carcinoma; SOB, shortness of breath; w, with; y, years.

Effectiveness was defined as at least 2 of the following 3 criteria being met: (a) improved clinical symptoms; (b) stable or improved complete blood count/immunological parameters; (c) improved performance status or body weight.

Data reported are from the most recent of the articles.

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 sweating, pain, palpitations and shortness of breath, insomnia, and anxiety,^14,15 while the third study found no change for cough, dyspnea, pain, fatigue, or other symptoms.²⁸

Effectiveness

Three studies used a composite endpoint termed effectiveness or effectiveness rating; in one study, this term was not defined,²⁴ while in the other two studies treatment was considered “effective” if at least two of the following three criteria were met: (a) improved clinical symptoms, (b) stable or improved complete blood count or immunological parameters, and (c) improved performance status or body weight.^14,15 Liu et al^14,15 found an overall effectiveness rating in the range of 82% to 85% compared with approximately 45% in the placebo groups (P < .001 for both),^14,15 while Nishiwaki et al²⁴ found no overall significant difference with PSK, but significantly greater effectiveness compared with chemotherapy only among patients with stage 3 but not stage 4 lung cancer.

Survival

One of two randomized controlled trials assessing survival endpoints demonstrated statistically significant results.^19,24 Ikeda et al¹⁹ found that PSK significantly increased 1-year survival compared with chemotherapy alone, 88.9% compared with 61.8% (P < .05). Neither of the two studies found significant effects on overall median survival, though Ikeda et al¹⁹ found significantly increased median survival among patients with stage 1 disease (P < .001).

Safety and Risks Associated With Use

No major adverse effects were reported in the studies reviewed above, including when PSK was administered to patients as long-term adjuvant therapy at a dose of 3 g daily for five or more years.¹⁷ There are no known contraindications for use during chemotherapy or radiation therapy. Coriolus has not been reported to affect clotting times. Some studies have reported no effect on platelet counts, while some report PSK offsetting the postchemotherapy decrease in platelets; however, there have been no reports of PSK decreasing platelet counts.^14,15,21,28 Coriolus extracts may shorten or reduce the degree of immunosuppression associated with chemotherapy, without deleterious effects on liver or kidney function.^17,28

Discussion

Important Findings

These results suggest that PSK may significantly improve immune function, tumor-related symptoms, and survival in patients with lung cancer, when used as adjunctive therapy alongside or following standard chemotherapy or radiation therapy, or surgery. PSK appears to increase the tolerability of chemotherapy and reduce limiting factors such as bone marrow suppression, while improving long-term survival. PSK appears to be effective particularly among patients with earlier stages of disease, and has been shown to significantly improve survival among patients with stage I, II, and III disease.^19,24 This notwithstanding, PSK has also been associated with improved survival of stage III patients when compared with stage II patients not receiving PSK.^16,17

Mechanism

PSK appears to exert its effects in large part through immune modulatory activity: increasing immune surveillance and offsetting chemotherapy induced bone marrow toxicity. Preclinical and human level evidence shows that PSK is able to reduce the depression of immune cells and immune cell activity following chemotherapy. This includes NK and phagocytic activity; numbers of lymphocytes, macrophages, neutrophils in bronchoalveolar lavage fluid; numbers of CD4+ and CD8+ cells in the thymus; and blood counts of white blood cells, hemoglobin, platelets, neutrophils, immunoglobulins, CD4+ counts, and NK activity.

Additional preclinical studies not related to lung cancer specifically show that PSK reduces tumor growth factor-β (TGF-β) and increases the antitumor response of peripheral blood mononuclear cells (PBMCs) to mitomycin-C (MMC)–treated cancer cells.⁴⁵ In addition, PSK was also able to enhance cytokine production (IL-2, IFN-γ, IL-4) in activated T-cells through activation of the T-cell receptor (TCR),⁴⁶ and enhanced the T-cell and splenocyte mitogenic response and macrophage tumoricidal activity.⁴⁷

Fisher and Yang⁴ suggest that PSK activates a number of immunological pathways converging on cancer cell inhibition, including stimulating T-cell cytokine secretion; activating macrophages and increasing tissue macrophages presentation of tumor antigen; stimulating thymus and bone marrow activity, B-cell production of antitumor antibodies; increasing NK cell and cytotoxic T-cell activity; as well as exerting direct antitumor effects. This model is supported by our findings.

PSK also possesses direct chemopreventive activity, decreasing tumor growth in vivo, and antimetastatic effects, decreasing cancer cell chemotaxis and adhesion, as well as decreasing degradation of collagen IV.^32,38-40

A recent 2012 review of the clinical and mechanistic anticancer effects of PSK found that the activity of PSK could be categorized in 3 ways.⁴⁸ First, PSK offsets immunosuppression induced by factors related to carcinogenesis, such as TGF-β, immunosuppressive acidic protein (IAP), prostaglandin E2 (PGE2), and IL-10, or as a result of cancer treatments, including surgery and chemotherapy. Second, PSK activates immune responses involved in antitumor effects, including maturation of dendritic cells (DCs) and activation of T cells, activation of NK cells, correction of Th1/Th2 imbalance, enhancement of B-cell antibody production, and promotion of IL-15 production by monocytes. Third, PSK enhances antitumor effects of chemotherapy by induction of apoptosis, inhibition of metastasis and neoangiogenesis, through direct actions on tumor cells.

Pharmacology

Pharmacokinetic studies have shown that PSK is partially digested in the gastrointestinal tract, and small molecular breakdown products are found in the bloodstream within two hours of ingestion.^4,49 Larger substances consistent with intact PSK are observed with four hours of ingestion, suggesting that these are absorbed through a slower uptake process such as pinocytosis.^3,4,49 PSK is distributed extensively in bone marrow, salivary gland, brain, liver, spleen, and pancreas tissue, and is excreted primarily through pulmonary expiration (70%) as well as urine (15% to 20%) at 24 and 72 hours, respectively.^4,50

Drug Interactions and Contraindications

Given that PSP and PSK exert their influence via stimulation of the immune system, coadministration of these polysaccharides with immunosuppressant medication may negate their effect.⁵¹ Furthermore, PSK and PSP may not be appropriate for individuals with autoimmune diseases or those receiving bone marrow transplants.⁵¹ Few adverse effects have been reported with the use of PSK^3,51; however, discoloration of the fingernails was noted in one study.^3,52 There are no investigations directly assessing impact on the pharmacokinetics of chemotherapeutics alongside coadministration of PSK; however, findings from studies investigating adjuvant use or co-administration are not suggestive of harm.

Strengths and Limitations

Limitations of our review include the fact that only 54% of the human trials (six of 11) included were randomized, possibly contributing to introduction of bias among the results. These studies nonetheless provide additional controlled evidence of PSK’s effects in a clinical setting. Some of the studies included are up to 30 years old. The standard of care for cancer patients has developed and improved cancer outcomes over this span of time. Despite recent advances, however, immunosuppression in particular remains a limiting factor in chemotherapy regimens, suggesting that use of PSK may remain relevant as an adjunctive therapy in lung cancer patients of varied stages. In addition, the benefit of immune stimulation may well exert important anticancer related activity. This is supported by a number of more recent studies corroborating the benefits of PSK.^{16,17,20,21,28}

Strengths of our review include its comprehensiveness in analyzing both English and Japanese language research, gray literature, as well as including preclinical level evidence. Future research should investigate the effects of PSK on survival, immune parameters, and cancer associated symptoms in a more rigorously designed clinical trial reflective of current practices.

The Coriolus extracts PSK and PSP appear to be safe and effective as long-term adjuvant immunotherapy in conjunction with or following standard chemotherapy and/or radiation, and may increase survival time, immune function, and tumor-associated symptoms in patients with lung cancer.

Footnotes

Declaration of Conflicting Interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by a knowledge synthesis grant from the Canadian Institutes of Health Research (CIHR). Deborah Kennedy was supported by a career development grant from the Sickkids Foundation.

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Polysaccharide K and Coriolus versicolor Extracts for Lung Cancer

Abstract

Keywords

Introduction

Methods

Results

Preclinical Evidence

Immunologic Activity and Chemotherapy-Induced Immune Suppression

Immune-Mediated Antitumor Activity

Nonspecific Antitumor Effect

Metastasis

Proliferation and Apoptosis

Nonrandomized Controlled Trials

Median Survival

One-, Two-, and Five-Year Survival

Randomized Controlled Trials

Immune Function

Performance Status and Body Weight

Cancer-Associated Symptoms

Effectiveness

Survival

Safety and Risks Associated With Use

Discussion

Important Findings

Mechanism

Pharmacology

Drug Interactions and Contraindications

Strengths and Limitations

Footnotes

Declaration of Conflicting Interests

Funding

References