U.S. patent application number 10/043485 was filed with the patent office on 2002-09-12 for method of treating malignancies and viral infections and improving immune function with a dietary supplement.
Invention is credited to Sun, Alexander S..
Application Number | 20020127243 10/043485 |
Document ID | / |
Family ID | 23378053 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020127243 |
Kind Code |
A1 |
Sun, Alexander S. |
September 12, 2002 |
Method of treating malignancies and viral infections and improving
immune function with a dietary supplement
Abstract
A dietary supplement comprising as its active ingredients
soybean, mushroom and mung bean is used in a method to in a method
to ameliorate at least one effective malignancy or viral infection
or to enhance immune functions. The active components of the
dietary supplement include phytoestrogens, .beta.-glucans,
saponins, inositol hexaphosphate, and lectins.
Inventors: |
Sun, Alexander S.; (Milford,
CT) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
3811 VALLEY CENTRE DRIVE
SUITE 500
SAN DIEGO
CA
92130-2332
US
|
Family ID: |
23378053 |
Appl. No.: |
10/043485 |
Filed: |
January 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10043485 |
Jan 10, 2002 |
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09350758 |
Jul 9, 1999 |
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Current U.S.
Class: |
424/195.15 ;
424/727; 424/728; 424/745; 424/754; 424/757; 424/764; 424/765;
424/769; 424/773 |
Current CPC
Class: |
A61P 31/12 20180101;
A61K 45/06 20130101; A61K 36/889 20130101; A61K 36/8962 20130101;
A61P 35/00 20180101; A61K 36/69 20130101; A61K 36/258 20130101;
A61K 36/185 20130101; A61K 36/232 20130101; A61K 36/288 20130101;
A23L 11/00 20160801; A61K 36/06 20130101; A61P 31/22 20180101; A61K
36/63 20130101; A23L 33/105 20160801; A61K 36/734 20130101; A23L
31/00 20160801; A61K 36/484 20130101; A61K 36/23 20130101; A61P
37/04 20180101; A61P 31/18 20180101; A61K 36/9068 20130101; A61P
35/02 20180101; A61P 31/16 20180101; A61P 43/00 20180101; A61K
36/07 20130101; A23V 2002/00 20130101; A61K 36/48 20130101; A61K
36/06 20130101; A61K 2300/00 20130101; A61K 36/07 20130101; A61K
2300/00 20130101; A61K 36/185 20130101; A61K 2300/00 20130101; A61K
36/23 20130101; A61K 2300/00 20130101; A61K 36/232 20130101; A61K
2300/00 20130101; A61K 36/258 20130101; A61K 2300/00 20130101; A61K
36/288 20130101; A61K 2300/00 20130101; A61K 36/48 20130101; A61K
2300/00 20130101; A61K 36/484 20130101; A61K 2300/00 20130101; A61K
36/63 20130101; A61K 2300/00 20130101; A61K 36/734 20130101; A61K
2300/00 20130101; A61K 36/889 20130101; A61K 2300/00 20130101; A61K
36/8962 20130101; A61K 2300/00 20130101; A61K 36/9068 20130101;
A61K 2300/00 20130101; A23V 2002/00 20130101; A23V 2200/308
20130101; A23V 2250/641 20130101; A23V 2250/21172 20130101; A23V
2250/208 20130101; A23V 2250/2136 20130101; A61K 36/69 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
424/195.15 ;
424/757; 424/727; 424/728; 424/764; 424/754; 424/765; 424/773;
424/769; 424/745 |
International
Class: |
A61K 035/84; A61K
035/78 |
Claims
1. A method to ameliorate at least one effect of malignancy or
viral infection which method comprises: administering to a subject
in need of such treatment an effective amount of a dietary
supplement comprising soybean, mushroom and mung bean or extracts
thereof, wherein said composition is administered periodically for
a time sufficient to achieve amelioration.
2. The method defined in claim 1 wherein said dietary supplement
further comprises at least one member of the group consisting of
red date, scallion, garlic, lentil bean, leek, hawthorn fruit,
onion, ginseng, angelica root, licorice, dandelion root, senegal
root, ginger, olive, sesame seed, and parsley, or extracts
thereof.
3. A method of enhancing immune functions comprising administering
to a subject an effective amount of a dietary supplement comprising
soybean, mushroom and mung bean or extracts thereof administered
periodically for a time to achieve enhanced immune functions.
4. The method defined in claim 3 wherein said dietary supplement
further comprises at least one member of the group consisting of
red date, scallion, garlic, lentil bean, leek, hawthorn fruit,
onion, ginseng, angelica root, licorice, dandelion root, senegal
root, ginger, olive, sesame seed, and parsley, or extracts
thereof.
5. The method defined in claim 1 wherein said method increases
CD4.sup.+ cell levels in said subject.
6. The method defined in claim 5 wherein said dietary supplement
further comprises at least one member of the group consisting of
red date, scallion, garlic, lentil bean, leek, hawthorn fruit,
onion, ginseng, angelica root, licorice, dandelion root, senegal
root, ginger, olive, sesame seed, and parsley, or extracts
thereof.
7. The method defined in claim 1 wherein said malignancy is
selected from the group consisting of non-small cell lung cancer,
small cell lung cancer, prostate cancer, breast cancer, stomach
cancer, small intestine cancer, colonrectal cancer, renal cell
carcinoma, soft tissue sarcoma, ovarian cancer, thyroid cancer,
acrcinoid tumors, sarcoma of the bone, melanoma, glioblastoma,
oligodendroglioma, astrocytoma, medulloblastoma, acute lymphomas,
chronic leukemias, cancer of unknown primary site, Hodgkin's
disease, and non-Hodgkin's disease.
8. The method defined in claim 1 wherein said viral infection is
selected from the group consisting of HIV, Epstein-Barr virus,
herpes, and influenza viruses.
9. A method to ameliorate at least one effect of malignancy or
viral infection comprising administering to a subject in need
thereof an effective amount of a dietary supplement comprising at
least one phytoestrogen, at least one .beta.-glucan, at least one
saponin, inositol hexaphosphate, and at least one lectin.
10. The method defined in claim 9 wherein the at least one
phytoestrogen is at least one member selected from the group
consisting of genistein, coumestrol, daidzein, and biochanin A;
wherein said at least one .beta.-glucan is at least one member
selected from the group consisting of lentinan, pachymaran,
zymosan, schizophyllan, KS-2, and pachyman; and said at least one
lectin is at least one member selected from the group consisting of
phytohemagglutinin and concanavalin A.
11. The method defined in claim 10 wherein the dietary supplement
comprises genistein, biochanin A, coumestrol, inositol
hexaphosphate, at least one beta-glucan and at least one lectin.
Description
TECHNICAL FIELD
[0001] This invention relates to treatments effective in treating
malignancies and restoring CD4.sup.+ cell levels, and also to
dietary supplements that improve immune functions. In particular,
it concerns compositions that are derived from plants, foods and
extracts thereof, that are used in a particular combination as
dietary supplements, which are effective against malignancies and
depressed immune functions and which improve overall immune
function.
BACKGROUND OF THE INVENTION
[0002] Nutritional support for cancer patients has been studied
extensively. It provided a substantial improvement in nutritional
status of cancer patients whose malnutrition was due to reduced
oral intake, but it fell short of its goals when the malnutrition
was due to malignancy. No improvement in the tumor's response to
therapy has been demonstrated by this approach, which primarily
manipulated protein and caloric intake in a generic strategy.
[0003] In the past three decades, studies have repeatedly shown
that some foods contain components with antitumor or
immune-enhancing activities. These components are nontoxic and have
different modes of action, and their individual antitumor
activities are modest. A partial list of these components is
presented in Table 1. The use of fruits and vegetables, which were
not specifically selected for their antitumor attributes and may
contain only a few of these components, for cancer prevention has
been recommended by the American Cancer Society and the National
Cancer Institute; their increased consumption is considered a major
cause for the reduction in cancer-related deaths in recent
years.
1TABLE 1 Non-toxic Antitumor Components in Plants.sup.1 Antitumor
Components Functions Protease inhibitors in soybean Suppress
chemically induced carcinogenesis in colon, anal gland, oral
cavity, lung, breast, and skin Autoclave-resistant factor in
Protection against metastasis of radiation-induced soybean thymic
lymphosarcoma and weight loss Plant sterols Protective effect
against tumorigenesis in colonic mucosa Saponin (found in soybeans)
Potentiation of rabies vaccine in mice Antitumor activity
Inhibition of induction of Epstein-Barr virus Genistein (found in
soybeans) Inhibits angiogenesis and growth of human prostate cancer
Biochanin A (found in soybeans & Inhibits human prostate cancer
mung beans) Other isoflavones Inhibit growth of human cancer cell
lines derived from gastrointestinal tract Inositol hexaphosphate
(found in Enhances NK cell activity and suppresses tumor soybeans
or mung bean) growth Suppresses tumor formation and growth Inhibits
growth of human leukemia cells and induces differentiation of K-562
cells .beta.-Glucans (e.g., lentinan) (found in Host-dependent
inhibition of sarcoma 180 cell mushrooms) growth
Immunoaccelerators, immunopotentiators, and immunomodulators
Enhance production of IL-1, TNF, LAK activity, cytotoxic T
lymphocytes, cytotoxic peritoneal exudate cells Lectins (found in
mung beans) Selective stimulation of T lymphocyte proliferation
.sup.1Abbreviations are as follows: NK, natural killer; IL-1,
interleukin-1; TNF, tumor necrosis factor; LAK,
lymphokime-activated killer.
[0004] Non-small cell lung cancer (NSCLC) causes the death of
>400,000 patients annually in the United States and Europe. The
benefit of conventional therapies for unresectable stage IIIB and
IV NSCLC patients is marginal; the generally accepted median
survival time (MST) of stage IV patients has remained 4-6 months
for the control group and 6-10 months for the treatment group, and
the one-year survival time is usually only 20%. Even stage I NSCLC
patients have a 52% death rate due to lung cancer within two years
when treated with radiotherapy alone. Clearly, more effective
therapies are needed.
[0005] With regard to AIDS patients, improvement in CD4.sup.+ cell
count has become a a major area of research in AIDS therapies.
Current therapies can not increase CD4.sup.+ counts to normal range
in the 12-month treatment period. Many patients are still dying
from depressed immune functions even when their serum HIV load can
be reduced to an undetectable level by antiretroviral therapy.
[0006] Continuous treatment with toxic antiretroviral drugs for a
long period of time has generated instances of intolerable
toxicity; many patients cannot continue these highly toxic
treatments. Therefore, it would be useful to the industry to
provide non-toxic treatments that are effective against
malignancies and viral infections.
DISCLOSER OF THE INVENTION
[0007] The invention is directed to a dietary supplement and a
protocol of administration that is used to treat malignancies and
viral infections and to otherwise improve overall immune function.
The dietary supplement is a selected vegetable (SV) composition
that is a freeze-dried commercial vegetable soup prepared by Sun
Farm Corporation (Milford, Conn.). It is a brown powder with a
slightly sweet taste. The ingredients of SV include soybean,
mushroom, mung bean, red date, scallion, garlic, lentil bean, leek,
hawthorn fruit, onion, ginseng, angelica root, licorice, dandelion
root, senegal root, ginger, olive, sesame seed, and parsley. Rather
than focusing on a single immune modulator, SV is a combination of
various kinds of herbs and vegetables selected for their specific
activities. Thus, immune function may be augmented in a concerted
effort.
BRIEF DESCRIPTION OF THE DRAWING
[0008] FIGS. 1a and 1b are graphs illustrating the growth of lung
tumors in BALB/c mice.
[0009] FIG. 2 is a CT scan of three metastatic brain lesions
illustrating their disappearances after the SV treatment.
[0010] FIG. 3 shows the median survival time of Stage III B and IV
non-small cell lung cancer patients in the pilot study.
[0011] FIG. 4a shows the right cerebellar metastasis of patient #9
in the pilot study.
[0012] FIG. 4b is a radiograph of a left scapula of patient #8 in
the pilot study.
[0013] FIG. 5 illustrates the survival times of stage III and IV
non-small cell lung cancer patients with and without the selected
vegetable treatment.
MODES OF CARRYING OUT THE INVENTION
[0014] The combination of SV as further described contains soybean,
mushroom, and mung bean as the active components. The remainder of
the components, red date, scallion, garlic, lentil bean, leek,
hawthorn fruit, onion, ginseng, angelica root, licorice, dandelion
root, senegal root, ginger, olive, sesame seed, and parsley are
added for flavor. The main active components of soybean, mushroom
and mung bean, are genestein, biochanin A, coumestrol, inositol
hexaphosphate, .beta.-glucans, and lectins.
[0015] Vegetables and herbs were selected for inclusion in SV on
the basis of two criteria: absence of toxicity and presence of one
or more known antitumor or immune-enhancing components as found in
Table 1.
[0016] One embodiment of the invention is a method to ameliorate at
least one effect of malignancy or viral infection comprising
administering to a subject in need of such treatment an effective
amount of the dietary supplement comprising soybean, shiitake
mushroom, and mung bean, wherein the composition is administered
periodically for a time to achieve amelioration.
[0017] Another embodiment of the invention is a method of enhancing
immune functions comprising administering to a subject an effective
amount of a dietary supplement comprising soybean, shiitake
mushroom and mung bean periodically for a time to achieve enhanced
immune functions.
[0018] Anti-viral effects such as increasing CD4.sup.+ cell levels,
have been found in patients from HIV, Epstein-barr virus, herpes,
and influenza viruses. In addition, malignancies such as small cell
lung cancer, non-small cell lung cancer, prostate cancer, breast
cancer, stomach cancer, small intestine cancer, colon rectal
cancer, renal cell carcinoma, soft tissue sarcoma, ovarian cancer,
thyroid cancer, acrcinoid tumors, sarcoma of the bone, melanoma,
glioblastoma, oligodendroglioma, astrocytoma, medulloblastoma,
acute lymphomas, chronic leukemias, cancer of unknown primary site,
Hodgkin's disease, and non-Hodgkin's disease have been successfully
treated with an administration of the dietary supplement in
accordance with the invention. Moreover, as this dietary supplement
is non-toxic and has immune enhancing properties, it can be used to
prevent immuno-suppressing diseases.
[0019] In general, the amounts of material administered are in the
range of those corresponding to 25-200 gms. of the soybean,
shiitake mushroom, and mung bean components and similar amounts of
the optional additives.
[0020] The dietary supplement can be in the form of a freeze-dried
product or extracts of the essential components along with the
flavorings. The freeze-dried material or extracts can be added to
water or other soup and administered orally on a regular basis. SV
can be boiled with water or soup and frozen for convenience and
then heated for use. About 10-50 mg per 50 kg body weight of the
freeze dried or net weight SV is preferable and about 30 mg per 50
kg body weight is more preferable. Thus, about 100-500 mg of about
a 10% SV mixture with a liquid per 50 kg body weight is preferable
and about 300 mg is more preferable. Preferably, the dietary
supplement should be administered once or twice daily.
Administration of 3 to 4 times a week is also acceptable.
[0021] In another embodiment, the present invention is directed to
the daily ingestion of nontoxic vegetables and herbs containing
known antitumor components that can improve clinical outcomes of
patients who already have advanced tumors. These observations
suggest the benefits of SV and led to the present invention.
[0022] Various species of mushroom can be used in the regimen of
the invention. Acceptable species include: Polyporus frondosus;
Polyporus giganteus; Polyporus umbellatus; Trametes cinnabarina.
However, the following are more preferable: Armillariella mellea;
Armillariella tabescens; Clitocybe nebularis; Lentinus lepideus
Fr.; Panus rudis Fr.; Pleurotus spodolencus Fr.; Pholiota adiposa;
Boletus erythropus; and Gyroporus castaneus. More preferred are:
Flammulina velutipes; Lepista luscina (Fr) Sing.; Lepista nuda
(Bull. ex. Fr.); Oudemansiella radicata; Tricholomopsis
platyphylla; Panellus stypticus; Pleurotus ostreatus; Schizophyllum
commune Fr.; Tricholoma gambosum; Agaricus arvensis; Coprinus
atramentarius; Coprinus comatus; Agrocybe paludosa; Agrocybe
praecox; Pholiota lubrica; Pholiota nameko; Rozites caperata;
Cortinarius bovinus Fr.; Cortinarius salor Fr.; Cortinarius
violaceus; Gymnopilus liquiritae; Rhodophyllus clypeatus;
Rhodophyllus sinuatus; Boletus edulis Bull.; Boletus pulverulentus;
Boletus regius Krombh.; Boletus rubellus Krombh.; Suillus
aeruginascens; Suillus bovinus; Suillus luteus; Lactarius
hygrophoroides; Lactarius volemus Fr.;Russula adusta Fr.; Russula
crustosa; Russula delica Fr.; and Russula lepida Fr. Especially
preferred are: Lentinus edodes; Panus conchatus; Tricholoma
matsutake; Tricholoma monolicum Imai; Agaricus bisporus; Agaricus
campestris; Cortinarius cinnamomeus Fr.; Cortinarius collinitus
Fr.; Cortinarius elatior Fr.; Cortinarius latus Fr.; and Lactarius
hatsudake.
[0023] A table of the properties of the various species
follows:
2 Percent Inhibition of Species Name Edible Tumor Growth Polyporus
frondosus yes 98% Polyporus giganteus yes 90% Polyporus umbellatus
yes 70% Trametes cinnabarina yes 90% Armillariella mellea yes 80%
cure ophthalmocopia Armillariella tabescens yes 70% Clitocybe
nebularis yes 80% Flammulina velutipes good 80-100% Lentinus edodes
excellent 80-97% Lentinus lepideus Fr. ywa 50-70% Lepista luscina
(Fr.) Sing. delicious yes Lepista nuda (Bull.) ex. Fr.) yes 90-100%
Oudemansiella radicata yes 80-90% Tricholomopsis platyphylla
Panellus stypticus yes 70-80% Panus conchatus yes 100% Panus rudis
Fr. yes 70% Pleurotus ostreatus yes 80% Pleurotus spodolencus Fr.
yes 72% Schizophyllum commune Fr. yes 100% Tricholoma gambosum yes
70-90% Tricholoma matsutake excellent 70-100% Tricholoma mongolicum
Imai excellent 70-100% Agaricus arvensis yes 100% Agaricus bisporus
excellent 100% Agaricus campestris excellent 100% Coprinus
atramentarius yes 100% Coprinus comatus yes 100% Agrocybe paludosa
yes 100% Agrocybe praecox yes 100% Pholiota adiposa yes 70-90%
Pholiota lubrica yes 100% Pholiota nameko yes 100% Rozites caperata
yes 70% Cortinarius bovinus Fr. yes 90% Cortinarius collinitus Fr.
yes 100% Cortinarius elatior Fr. yes 80% Cortinarius latus Fr. yes
100% Cortinarius salor Fr. yes 90% Cortinarius violaceus yes 100%
Gymnopilus liquiritae yes 90% Rhodoplzyllus clypeatus yes 100%
Rhodophyllus sinuatus yes 100% Boletus edulis Bull. yes 90-100%
Boletus erythropus ? 100% Boletus pulverulentus yes 90% Boletus
regius Krombh. yes 90% Boletus rubellus Krombh. yes 90% Gyroporus
castaneus yes 80% Suillus aeruginascens yes 100% Suillus bovinus
yes 100% Suillus luteus yes 90% Lactarius hatsudake yes 100%
Lactarius hygrophoroides yes 70% Lactarius volemus Fr. yes 90%
Russula adusta Fr. yes 80% Russula crustosa yes 70% Russula delica
Fr. yes 100% Russula lepida Fr. yes 100%
[0024] The active components in the SV comprise phytoestrogens,
.beta.-glucans, saponin, inositol hexaphosphate, and lectins.
Phytoestrogens such as genistein, coumestrol, daidzein, and
biochanin A are each present in the SV based on daily oral
consumption of about 1 mg-5 g/100 kg of body weight. .beta.-glucans
such as lentinan, pachymaran, zymosan, schizophyllan, KS-2, and
pachyman are each present in SV based on a daily oral consumption
in an amount of about 1 mg-5 g/100 kg of body weight. Saponins and
inositol hexaphosphate are each present in the SV based on daily
oral consumption of about 1 mg-5 g/100 kg of body weight. Lectins,
such as phytohemagglutinin and concanavalin A are each present in
the SV based on daily oral consumption of from about 1 mg-5 g/100
kg of body weight.
[0025] The following examples serve to illustrate, but not to
limit, the invention.
[0026] The first example that follows illustrates the influence of
selected vegetables (SV) that contain known antitumor components on
the survival of stage III-IV non-small cell lung cancer (NSCLC)
patients. All patients were treated with conventional therapies. SV
was added to the daily diet of 5 stage I patients in the toxicity
study group (TG) and 6 stage III and IV patients in the treatment
group (SVG), but not to the diet of 13 stage III and IV patients in
the control group (CG). Age, Karnofsky performance status (KPS),
and body mass index of SVG and CG patients were comparable at
entry. KPS declined in the CG patients (79.+-.8 to 55.+-.11) but
improved in the SVG patients (75.+-.8 to 80.+-.13) one to three
months after entry. Weight change in the CG, SVG, and TG patients
was -12.+-.5%, -2.+-.2%, and +4.+-.4%, respectively. The median
survival time and mean survival of the CG patients were 4 and 4.8
months, but in the SVG patients they were 15.5 and 15 months
(p<0.01). No clinical signs of toxicity were found in the TG
patients in the 24-month study period. Adding SV to the daily diet
of NSCLC patients was found to be nontoxic and associated with
improved weight maintenance, KPS, and survival of stage III and IV
NSCLC patients.
Example 1
Pilot Study of a Selected Vegetable Diet in Tumor Bearing Mice and
Stage IIIB and IV Non-Small Cell Lung Cancer Patients.
Method
[0027] SV Preparation. SV was prepared by Sun Farm Corporation,
Milford, Conn., employing "The Good Manufacturing Practices"
designed to guarantee minimal contamination with heavy metals and
bacteria (U.S. Federal Code of Regulations, Title 21, Part 100-69.
1996; U.S. Government Printing Office, Washington, D.C.). The
ingredients of SV include: soybean, mushroom, mung bean, red date,
scallion, garlic, lentil bean, leek, Hawthorn fruit, onion,
ginseng, angelica root, licorice, dandelion root, senegal root,
ginger, olive, sesame seed, and parsley. The mixture was boiled and
then stored frozen at -20.degree. C. and thawed at room temperature
before use.
[0028] Nutritional Data and Toxicity. Random samples of SV were
sent to Northeast Laboratory, Berlin, Conn., for analysis of
nutritional value, heavy metals, and bacteria.
[0029] Phytoestrogens: The assay was modified from Franke et al.
(Franke A A, Custer L J, Cema C M, Narala K K. Quantitation of
phytoestrogens in legumes by HPLC. J. Agric Food Chem 1994; 42:
1905-13). One gram of freeze-dried SV (DSV) was dispersed in a 50
ml mixture of HCl/ethanol/butylated hydroxytoluene (10/40/0.25,
v/v/v), refluxed for 2 h, filtered, and 5 .mu.l of the filtrate was
analyzed with HPLC (Nova-Pak 150 mm x 3.9 mm reverse phase C18
column, Waters, Milford, Mass.). The column was eluted with a
gradient from 5% to 50% acetonitrile in acetic acid-water (1/9,
v/v) in 15 min at 1 ml/min followed with 7.5 min wash with 50%
acetonitrile in the same buffer. Molar extinction coefficients
(daidzein, 20,893 at 250 nm; genistein, 37,154 at 263 nm,
coumestrol, 22,300 at 339 nm) were used for quantitative
determination.
[0030] Inositol: DSV (5 g) was incubated with 10 ml of 0.33N HCl
for 2 h, filtered, and diluted with deionized water (1:1, v/v) .
Inositol hexaphosphate was determined according to Ellis et al.
(Ellis R. Morris E R, and Philpot C. Quantitative determination of
phytate in the presence of high inorganic phosphate. Anal Biochem
1977; 77:536-9.)
[0031] Mouse Lung Tumor Model: Four week-old BALB/c male mice were
divided into groups of 5 (Experiment I) or 8 (Experiment II) mice.
Mice in each group were fed one food preparation a week prior to
tumor inoculation and during the entire study period.
[0032] BALB/c Line 1 Lung tumor cells (104 cells; viability over
90%) were injected subcutaneously in the right thigh. Tumor size
was measured every 2-4 days. Experiment I: Food #1 was made from
Lab Chow powder, mixed with water, made into pellets, and
air-dried. Food #2, 190 3, and #4 were made as above and mixed with
a hot water extract of mung bean (#2: 10% by wt; Lab Chow, 90%),
shiitake mushroom (#3: Lentinus edodes, 10% by wt), or both at the
same concentrations (#4). Experiment II: Lab Chow powder (#5,
Control) was mixed with freeze-dried SV (DSV) powder (#6:5% wt/wt).
Food consumption per group was measured weekly.
[0033] Clinical Study Design. Sixteen patients with knowledge of
the lead cases requested SV as a nutritional supplement and
volunteered their participation. The study period was 60 months
from February, 1992 to January, 1997. Patients were treated with
conventional therapies selected by their physicians and added SV to
their daily diet. Their clinical status was monitored by their
physicians and verified by the authors. Only 14 stage IIIB and IV
patients who ingested SV daily for 2 months or longer were included
in the study group. Karnofsky performance status (KPS) was recorded
before the use of SV and 5 months later. The four patients who
ingested SV less than 2 months were excluded from analyses.
Patients #1 and #2 provided retrospective data; they were excluded
from the statistical analyses.
[0034] Diagnosis, Staging, and Survival Time. All the patients were
diagnosed in their local hospitals. The pathological slides were
reviewed by the pathologist (TMF) and radiographs by the
radiologists (YPH and HCY). Staging was determined according to the
revised International System for Staging Lung Cancer. The survival
time was calculated from the date of diagnosis of stage IIIB or IV
NSCLC to the date of death or to the cut-off date.
[0035] Ingestion of SV. SV is a grayish green paste with a slightly
sweet taste. It was ingested daily (approximately 283 g) by
patients as part of breakfast or lunch either directly, or mixed
with other foods.
[0036] Materials: All chemicals were reagent grade. Genistein,
daidzein, inositol, inositol hexaphosphate, butylated
hydroxytoluene, and O-toluidine were obtained from Sigma Aldrich
Chemical Co. (St. Louis, Mo.), coumestrol, acetonitrile, acetic
acid, trichloroacetic acid, and thiourea from Fisher Scientific
(Pittsburgh, Pa.). Purina Lab Chow powder from Purina Mills
(Richmond, Ind.), BALB/c mice from Charles River Laboratories
(Wilmington, Mass.), and SV from Sun Farm Corporation (Milford,
Conn.).
[0037] Informed Consent: All patients were informed of the
ingredients in SV and that these ingredients have been used widely
as foods or food flavors. They used SV daily as a food supplement,
and gave written permission to the authors to review their medical
records.
Results
[0038] Nutritional Value and Hazardous Contaminants of SV. The
daily dose of SV contains a net wet weight of 283 grams;
physiological fuel calories, 87+3; protein, 10+2 g; carbohydrate,
11+2 g; total fat, <1 mg; cholesterol, <1 mg; dietary fiber,
12+1 g; vitamin C<0.1 mg; vitamin A, <15 IU; thiamine, <4
mg; riboflavin, 45+4 mg; sodium, 45+4 mg; calcium, 9+1 mg;
potassium, <1 mg; iron, <5 mg. Heavy metal content and
culture plate counts of samples of SV were: arsenic <1 (PPM);
cadmium, <1.3; barium, <1; chromium, <2.7; lead, <1.7;
mercury, <0.1; silver, <1.3; yeast and mold count (per gram),
<10; E. coli, <1; and standard plate count, <10. These
levels are well below allowable levels.
[0039] Antitumor Components in SV: The following components were
measured in SV (mg/283 g SV/ daily dosage): inositol hexaphosphate,
63+6; genistein, 2.6+0.1; daidzein, 4.4+0.1; coumestrol,
15.5+0.4.
[0040] Mouse Lung Tumor Model: In Experiment I, tumor size was
measured on the 10th, 12th, 14th, 17th, and 22nd day after the
inoculation of tumor cells (FIG. 1A). Curves #1, #2, #3, and #4 in
FIG. 1A depict the mean tumor size in mice consuming Food #1, #2,
#3, and #4 respectively measured after inoculation. Each point is
mean+SE. The percent inhibition of tumor growth rate in groups #2,
#3, and #4 compared with the control (#1) were 16%, 49%, and 82% on
the 14th day and 53%, 60%, and 82% on the 22nd day respectively.
Both mung bean (#2) and mushroom extract (#3) showed clear
inhibition of tumor growth and these effects were additive when
both extracts (#4) were used in combination. In Experiment II,
tumor size was measured on the 14th 16th, 19th, 21st, and 23rd day
after tumor inoculation (FIG. 1B). Curves #5 and #6 in FIG. 1B are
the mean tumor size in mice using Food #5 and #6. Each point is
mean+SE. Lab Chow containing 5% DSV produced 53-74% inhibition in
tumor growth rate in the first 23rd days. One of 8 mice showed
partial tumor regression after 26th day and complete regression
after 32days. The weekly food consumption per mouse of preparations
#1 to #6 was 16.9+1.4 g, 18.9+0.8 g, and 16.0+0.6 g in the first,
second, and third week after tumor inoculation. No appreciable
difference between groups was found.
[0041] Patient Characteristics: The patients' gender, age, stage,
cell type, metastatic sites, conventional treatments to the primary
tumor and metastatic lesions respectively, tumor response,
complications, and KPS are summarized in Table 2. Occurrence of
metastatic disease after ingesting SV, the length of time taking
SV, the duration of tumor-free status, and survival are also
summarized in Table 2.
3TABLE 2 Patients Characteristics and Survival Time with Adjuvant
SV to Therapy (Months).sup.*3 . Treatments New T Time Tumor Stage
Cell Metastatic Primary Metastatic Tumor Other after KPS .sup.*2
using Case/Sex/Age T.N.M. Type Site Tumor Tumors Response.sup.*1
Complication SV (a) (b) SV. Free Survival A. Lead Cases: 1 F 69 IV:
2.2.1. Irg adrenal S C, R, SV, smancs, S no residual T no no 40 100
27 <133 <137 alive 2 F 75 IV: 2.1.1 adn brain S SV, R, smancs
complete malnutrition.sup.P2 no 40 80 17 10 14 B. Study Group a.
Complete Response of Metastatic Tumors and No Recurrent Tumor After
Using SV Alone 3 F 57 IV: 1.3.1. adn both lungs S SV complete no no
50 100 <35 <30 <39 alive 4 F 73 IV: 1.3.1. adn both lungs
S SV complete no no 90 100 <27 <12 <28 alive b. Complete
Response, Partial Response, or Stabilization of Metastatic Tumor
after Using SV and Other Treatments 5 F 80 IV: 4.2.1. adn vert,
pleu ef R R, SV stable/prog no no 50 90 <46 0 <48 alive 6 M
67 IIIB: 4.2.0. adn pleural eff no PD, SV, R, C partial nerve
injury.sup.P6 yes 50 90 43 0 45 7 F 34 IIIB: 2.3.0. nsc contral
l.n. S C, SV, R, no residual T no no 50 100 <32 <30 <33
alive 8 F 78 IIIB: 4.0.0. adn pleural eff S R, C, SV stable
pneumonia no 50 100 <21 <20 <28 alive 9 M 69 IV: 2.0.1.
adn brain, bone S R, SV complete no yes 50 100 16 na 22 10 F 51 IV:
1.2.1. adn brain S, C, R SV, R, S no residual T depression.sup.P10
yes 50 90 14 na 20 11 F 59 IV: 1.1.1. adn brain no SV, R
stable/prog v. thrombosses.sup.P11 no 50 90 10 0 11 12 M 58 IV:
2.3.1. adn adrenal S, C C, SV, C stable/prog heart.sup.P12 no 60 70
9 0 12 13 F 76 IIIB: 4.3.0. adn pleural eff S C, R, SV complete no
no 50 100 5 2 <8 alive 14 F 47 IIIB: 4.3.0. adn pleural eff C C,
SV na na 50 50 5 0 6 Average Karnofsky Performance Status (Pts #3-
#14) 54 .+-. 12 90 .+-. 15 C. Ineligible Patients.sup.*4 15 M 40
IIIA: 1.2.0. adn C, R SV nausea, vomiting 1.5 0 10 16 M 56 IV:
4.0.1. sqm vert R R, SV paraplegia 1.4 0 5 17 M 64 IV: 4.0.1. adn
brain, bone S, C SV 0.2 0 6 18 M 57 IV: 4.0.1. adn spine, rib C, R
SV 0.5 0 3 Tumor Response.sup.*1: No Tumor: Patient had no
detectable tumor subsequent to surgical resection. Complete:
Complete regression. Stable: Tumor stopped growing. Stable/prog:
Tumor was stable first and then progressed. Partial: Partial
ewfewaaion. KPS.sup.*2: Karnofsky Performance Scale; (a) KPS at the
time of starting SV. (b) KPS after using SV for 5 months or more.
Time (Months).sup.*3: Months ingesting SV, remaining tumor free, or
surviving at last observation. Ineligible Patients .sup.*4 Pt #15,
17, 18 ingested SV at less than full dosage and Pt #15-18 for less
than 2 months. These patients did not meet the entry criteria and
were excluded from the evaluation of MST. Abbreviations: Lrg: Large
cell carcinoma. nsc: non-small cell carcinoma; adn.:
adenocarcinoma; sqm. : squamous cell carcinoma. S.: surgery; C:
chemotherapy; R: radiotherapy; PD: pleurodesis; pleural eff:
pleural effusion; vert: vertebrae; v: vein. l.n.: lymph node(s);
na: data not available. P2: Patient had anorexia and severe and
severe malnutrition during smancs therapy and died from aspiration
pneumonia. P6: Patient suffered severe pain due to
pleurodesis-related thoracic nerve injury. He was treated with
Elavil, ibuprofen, atenolol, Fentanyl, Decadron, and bupivacaine.
P10: Patient was treated with Decadron, Klonopin, methadone,
Elavil, and Duragesic. P11: Patient suffered extensive deep vein
thromboses and was treated with Decadron and phenobarbital after
her tumor was stabilized. p12: Patient had coronary artery bypass
surgery.
[0042] Lead Cases:
[0043] Case #1: A stage Impatient whose tumor progressed while on
chemotherapy and radiotherapy has been tumor-free for 133 months
after ingestion of SV, SMANCS therapy, and resection of a
metastatic lesion.
[0044] Patient #1 had a poorly differentiated large cell carcinoma
in her RLL (2.2.times.2 cm) with a positive subcarinal lymph node
(Table 2). A lobectomy in 1/85 was followed with methotrexate,
adriamycin, CCNU, and cytoxan. Her disease progressed with
metastasis to left adrenal gland (4.times.3 cm, 8/85), a right
pleural effusion developed, and her KPS dropped to 40. Her adrenal
tumor did not respond to radiotherapy and continued growing
(5.times.4 cm, 11/85). She began ingesting SV daily from 9/85. She
was also treated with SMANCS, which is the antitumor protein,
neocarcinostatin, conjugated with a polystyrene-maleic acid
copolymer (35), and had adrenalectomy in 12/85. The adrenal tumor
was well encapsulated containing mostly necrotic tissue. She
continued SMANCS for 4 months and ingested SV daily until 12/87.
She remains tumor-free.
[0045] Case #2: Complete regression of three metastatic brain
tumors
[0046] Patient #2 had a well differentiated adenocarcinoma in RUL
(Table 2). She had a lobectomy in 3/86. In 10/86, CT scan showed 3
metastatic brain lesions (FIG. 2). KPS was 40. She started SV,
SMANCS, and a one month course of radiotherapy. All 3 tumors
disappeared completely in 4 months. She continued SV and SMANCS
therapy until 6/87. During this time she developed anorexia and
severe malnutrition, followed by aspiration pneumonia and sepsis,
and died in 12/87 without clinical signs of tumor recurrence.
[0047] Median Survival Time: Five stage IIIB and 7 stage IV
patients were eligible for analysis (Patients #3-14). Half of these
patients were still alive at the closing date; thus, the MST was
not reached according to Kaplan and Meier (Kaplan E L, Meier P.
Nonparametric estimation from incomplete observations. J Am Stat
Assoc 1958; 53: 457-82). A conservative estimate of 33.5 months,
namely, the midpoint of the survival curve above the median, i.e.,
between 22 and 45 months, was chosen as the MST (FIG. 3). As shown
in FIG. 3, the survival of 12 patients (#3 to #14, Table 2) was
plotted and analyzed according to Kaplan and Meier. The MST should
be 45 months and the 95% confidence interval had a lower boundary
of 12 months and no upper boundary reached. For conservative
evaluation, the midpoint of the survival curve above the median was
chosen as MST, namely, between 22 and 45 months or 33.5 months. The
95% confidence interval had a lower-boundary of 12 months and no
upper-boundary. One-year survival was 75%.
[0048] New Tumors: Ten of the 14 patients (#1-5, 7, 8, 11-13, Table
2) had no new sites of metastasis after conventional treatments and
SV therapy. Patient #14 suffered severe side-effects of concurrent
chemotherapy and was not evaluated for new tumors.
[0049] SV Therapy Alone: Both patient #3 and #4 had complete
regression of their multiple metastatic lesions in both lungs after
using SV alone for 5 and 15 months and remained tumor-free, 39 and
28 months after diagnosis. After unsuccessful radiotherapy and
while using SV alone, the pulmonary and vertebral body lesions of
patient #5 were stable for 40 months and subsequently progressed
slowly. She was still alive at the conclusion of this study.
[0050] SV and Radiotherapy: Of the four patients who had brain
metastases, three (#2, #9, 10) achieved complete regression after
using SV and radiotherapy. Both lesions in brain and bone of
Patient #9 regressed completely after radiotherapy. FIG. 4 is a
right cerebellar metastasis of patient 9. FIG. 4A shows in A is a
post contrast CT scan in superior orbitomeatal plane taken on Dec.
17, 1992. An enhancing metastatic lesion (T) of 1.5x1.2x
approximately 1.2 cm in size, located in the quadrangular lobule of
the cerebellum on the right side with considerable edema (low
density area) of the surrounding area, particularly
anteriomedially. The fourth ventricle (4) was displaced anteriorly
and to the left. The vermis (V) was also displaced to the opposite
side. The posterior fossa cisterns were narrow on the right
(unlabelled double arrow). FIG. 4A also shows B and C, which shows
a post gadolinium MR section in exaggerated inferior orbitomeatal
plane taken on Jun. 16, 1994. Because of considerable difference in
sectional angles between A and B & C, two consecutive MR
sections (B &C) were selected in order to amply cover the
original site of the cerebellar metastasis. The enhancing tumor
attenuated and was no longer detectable in post gadolinium axial MR
T1 weighted image. Unlabelled single arrow in two consecutive MR
images indicates the presumptive location of the original
cerebellar metastatic lesion seen in A. The fourth ventricle (4)
and the vermis (V) have returned to their normal positions. The
edema surrounding the tumor seen before the treatment was not
observed. FIG. 4B is a radiograph of the left scapula of patient
#8. In A, the radiograph of left scapula shows a mixed osteoblastic
and osteolytic lesion (white arrowhead) in the inferior aspect of
the glenoid process, due to metastatic cancer. In B, the radiograph
of left scapula 12.5 months later shows that the lesion in the
glenoid process has much improved. Patient #11 had radiotherapy to
her left cerebellar brain lesions; her primary tumor and the
multiple lesions in her brainstem remained stable without
radiotherapy for 10 months.
[0051] Toxicity and Performance Status: Patients ingested SV daily
for 5 to 46 months. Except for patient #14 whose condition was
adversely affected by concurrent chemotherapy, all patients in the
cohort (#3-#13) showed no toxic complications attributable to SV.
Their blood chemistry values revealed no compromise in
hematological, renal, hepatic, and metabolic function; they all
showed a significant improvement in KPS after ingesting SV for 5
months (Table 2). Average KPS values increased from 54+12 to 90+15
(p<0.01).
Discussion
[0052] The benefits of fruits and vegetables for cancer prevention
has been emphasized by both NCI and ACS and are considered as major
causes of the reduction in cancer rates and related deaths. The
present report describes the pursuit of an unexpected clinical
observation and provides data suggesting that a mixture of edible
plants, specifically selected for their antitumor attributes, may
benefit patients who already have advanced cancer.
[0053] The MST of stage IIIB and IV NSCLC has changed little in
recent decades. Therefore, historical controls can be used to
provide comparison for the results observed here. In a review of 8
randomized trials of chemotherapy versus supportive care for stage
III-IV NSCLC, the MST's of the untreated groups were 5 months or
less and 7-8.5 months in the chemotherapy groups (4). The MST for
the 12 patients who used SV for 2 months or longer was 33.5 months.
The sample size was small, but all patients had advanced disease;
moreover, objective responses to SV were observed in this cohort
and in one tumor-bearing mouse.
[0054] NSCLC patients with CNS metastases have a MST of 3-4 months
with radiotherapy and complete regression is rare (39-41). Of 4
patients with CNS involvement, three (#2, 9, 10) had complete
remission of CNS lesions and the fourth (#11) had a partial
response after radiotherapy and SV use. The complete regression of
metastatic tumors in both brain and bone (#9), and multiple brain
lesions (#2) is unexpected. Recurrence of malignant pleural
effusions and new metastases are common in stage III-IV patients.
Ten of 14 patients developed no new metastatic sites during this
study period.
[0055] Patient selection bias is a major consideration in clinical
trials. It is essential to consider sources of potential bias
especially when clinical outcomes differ markedly from historical
controls. Four patients (#15-18) who ingested SV for less than 2
months were not included in the survival analysis; their survival
times (3 to 10 months) were within the expected historical range.
Other possible bias could result from the self selection of highly
motivated patients who sought new treatments after failing to
benefit from conventional therapies and who were willing to make a
commitment to daily SV use often with strong family support.
Cassileth et al. report a weak link between cancer survival and
social ties, but these authors concluded that clinical factors
(e.g. stage, KPS, weight loss) but not psychosocial factors (e.g.
"hopefulness") could be considered predictors of survival. Whereas
patient compliance may be related to treatment efficacy,
psychological factors alone are unlikely to result in a three-fold
increase in MST or in complete tumor regression in patients using
SV alone. The inhibition of tumor growth observed in the mouse
model further supports the hypothesis that some combination of
ingredients in SV may have direct anti-tumor or immune modulating
activity.
[0056] Large clinical trials of advanced NSCLC often have a small
number of patients with long survivals. It could be argued that by
chance or selection bias such patients were overrepresented in this
cohort. This is unlikely because of many instances of poor
prognostic status and failed treatment history in this cohort when
SV was initiated. Furthermore, complete and partial tumor
regression and improved KPS after using SV alone are objective
responses to SV, which are not affected by patient differences or
by patient number. The potential causes of long survivorship have
received relatively little attention, although such studies may
yield clues for improved cancer treatment. Among these possible
causes, diet supplements are widely accessible and some are
supported by scientific studies. This approach, which uses a
specific dietary supplement, was ingested by the 2 lead patients
and this cohort.
[0057] Well-known prognostic indicators for survival in NSCLC
include stage of disease, KPS, and weight loss. KPS values
increased from an average of 54+12 to 90+15 in 5 months after SV
use. In a prior study, the KPS of stage III and IV NSCLC patients
of SV-treated group also improved but it decreased in the untreated
control group; similarly the MST also improved significantly
(3-fold). Body weight data were not available in the current study.
In the prior study, however, the weight change was -2.1+2.3% in the
SV-treated group but -11.6+4.9% in the control group. In both
studies, blood chemistries revealed no evidence of toxicity in
patients ingesting SV daily for 5-46 months. Significantly improved
performance status and absence of toxicity are concordant with the
prolonged survival times of these patients.
[0058] The immunostimulatory and antitumor effects of purified
beta-glucans (e.g., lentinan, pachymaran, zymosan, schizophyllan)
and peptidomannan (KS-2) have been well documented. Other studies
have identified antitumor actions of soybean components, e.g.,
protease inhibitors, inositol hexaphosphate, coumestrol, daidzein,
biochanin A, and genistein. Four of these components were
quantitatively identified in SV; others are reported to be present
in the vegetables contained in SV. The most abundant ingredients in
SV are soybean, mushroom, and mung bean. Because Purina Lab Chow
already contains soy protein, the antitumor activities of mushroom
and mung bean were tested individually and in combination.
Combining mushroom and mung bean extracts produced the greatest
inhibition of tumor growth (82%) in the mouse model indicating that
certain combinations of foods may be more carcinostatic.
[0059] The multiple instances of tumor response coupled with
increased survival times, attenuation of disease progression, and
consistent improvement in performance status indicate that SV
therapy, as an adjuvant to surgery and radiotherapy, should be
evaluated further in a large, randomized study of NSCLC
patients.
Example 2
Phase III Study of Stage III and IV Non-Small Cell Lung
Patients
[0060] Selection of Patients
[0061] All the stage III and IV NSCLC patients who first attended
the Lung Clinic, School of Medicine, University of Palacky, from
June 1992 to January 1994 and met the entry criteria were invited
to participate in the study. All eligible patients who did not use
SV served as the control group (13 patients). Cooperative group
phase II-III investigation entry criteria were used: .ltoreq.70
years of age; ability to eat well; adequate gastrointestinal,
hepatic, renal, and cardiopulmonary function; and Kamofsky
performance status (KPS).ltoreq.70. Exclusion criteria were white
blood cells<4,000/ml, platelets<100,000/ml, bilirubin>1.5
mg/dl, creatinine >1.5 mg/dl, blood sugar>200 mg/dl, prior
malignancy, myocardial infarction, uncontrolled hypertension,
arrhythmia, serious infection, psychiatric disorder, unreliability,
or noncompliance. In addition to the entry criteria, prognostic
factors for survival, including stage, previous and concurrent
therapies, tumor cell type, age, gender, KPS, and body mass index
(BMI) were compared in all groups. Twelve patients agreed to ingest
SV: six at stage In and IV in the treatment group (SVG) and five at
stage I in the toxicity study group (TG); one patient was first
diagnosed as having adenocarcinoma but was excluded from analyses
because she was later identified as having colon cancer in 1983.
All patients were offered standard conventional therapies. Patients
were followed until death or 24 months from the date of entry.
[0062] Study Period, Survival Time, and Statistical Analyses
[0063] This study was designed to test the null hypothesis
(H.sub.0) that the median survival times of the stage III and IV
patients in the treatment group (SVG) and the control group (CG)
will be the same. The alternative hypothesis (H.sub.2) is that the
MSTs of the two groups will be different. The study period was 24
months from the starting date (date of diagnosis). The survival
time was calculated from the starting date to the date of death or
to the cutoff date. The Kaplan-Meier method and log-rank test were
used to calculate and compare the median survival times and the 95%
confidence intervals. The Wilcoxon Rank and Sum test was used to
compare mean survival times between the two groups. Student's
t-test was used to compare the ages, KPS, and percent weight
change.
[0064] Diagnosis, Staging, and Survival Time
[0065] NSCLC was diagnosed by histopathology and/or cytopathology
and reviewed by a pathologist. The size and location of the tumors
were determined with radiographs by the treating physicians and a
radiologist and reviewed by another radiologist. Staging was
assigned according to the American Joint Committee on Lung Cancer.
The most conservative interpretation was used for analyses.
[0066] Treatment
[0067] All patients were treated with conventional therapies,
including radiation, surgery, and/or chemotherapy, selected by the
treating physicians independently of the use of SV. SV was included
as part of the daily diet of the treatment group patients. The
intended duration of treatment with SV was 24 months; participating
patients were encouraged to ingest SV soon after diagnosis and for
the entire period. All eligible patients who ingested SV were
included in the analyses.
[0068] Thirty grams of freeze-dried SV powder were mixed with one
cup of water or other soup and ingested daily. Patients were
interviewed and examined monthly, except for four patients
(Patients 5, 6, 8, and 10, Table 2) who were unable to keep their
clinical appointments. Computed tomography scans were performed at
entry and then every six months or sooner if clinically needed.
Body weight and KPS were evaluated at the study entry and one to
three months thereafter. Chest films, spirometry, and blood
chemistry were performed at entry and when clinically required or
bimonthly.
[0069] Nutrition Data
[0070] Random samples of SV were sent to Northeast Laboratories for
determination of their nutritional values. A 30-g daily serving of
SV (dry weight), on the basis of percentage of daily requirement of
a 2,000-calorie diet contains 11 g (4%) carbohydrate, 11 g (24%)
protein, <1 mg fate, 8 g (36%) dietary fiber, <1 mg
cholesterol, 102-110 cal gross food energy, and 84-90 cal
physiological fuel value.
[0071] Toxicity
[0072] The toxicity of SV was evaluated in all patients who had
ingested SV. To minimize the confounding effects of advanced
disease and therapeutic toxicity, five stage I NSCLC patients were
invited to take SV daily. Their clinical status was evaluated
monthly, and blood chemistries were obtained at entry and
bimonthly. Clinical signs of toxicity, such as fatigue, vomiting,
nausea, diarrhea, fever, headache, hair loss, mucosal ulcerations,
and skin rashes were evaluated. In addition, changes in appetite
and in the frequency of sexual activity and exercise before and
after diagnosis of NSCLC and before and after taking SV daily were
also evaluated.
[0073] Informed Consent
[0074] The protocol for the clinical trial was approved by the
Committee for Research on Human Subjects at the University of
Palacky School of Medicine. Informed consent was obtained from all
patients in the treatment and toxicity study groups.
[0075] Patient Characteristics
[0076] The control group (CG) consisted of five patients at stage
IV, four at stage IIIB, and four at stage IIIA (Table 2). The age
of the patients was 40-65 years, with an average of 54.3.+-.8.8
years. At entry their body mass index (BMI) was 19.5-36.5, with an
average of 26.7.+-.5.5, and their KPS was 70-90, with an average of
78.5+8.0. Thirty-one percent of the CG patients were women. In the
treatment group (SVG), 6 patients were eligible: one was a woman,
two were at stage IV, three at stage R IIIB, and one at stage IIIA
(Table 3). Their age was 41-55 years, with an average of
49.2.+-.4.7 years. At entry their BMI was 24-30.7, with an average
of 27.0.+-.2.7, and their Karnofsky performance scale (KPS) was
70-90, with an average of 75.+-.8.4. Student's t-test was used to
compare the age, BMI, and KPS at entry of the SVG patients with
those of the CG patients, yielding p>0.1.
[0077] Five stage I patients were in the toxicity study group (TG)
(Table 3). At study entry their age was 41-68 years, with an
average of 54.6.+-.11.3 years; their BMI was 22.2-27.7, with an
average of 24.7.+-.2.4; and their KPS was 70-90, with an average of
78.0.+-.8.4. One other patient (Patient 12, Table 3) had colon
cancer in 1983 and was presumed to have metastatic colon cancer on
review and was excluded from the analyses.
[0078] Weight Change
[0079] At entry BMIs of CG, SVG, and TG patients were 26.7.+-.5.5,
27.+-.2.7, and 24.7.+-.2.4, respectively (p>0.1, Student's
t-test). None of the patients was severely underweight, and all
BMIs were>19. The body weight of nine CG patients was measured
one to three months after entry (except for Patient 1), and all
lost 3.7-17.7% of their body weight, with an average loss of
11.6.+-.4.9% (Table 2). In the SVG patients who did not receive
chemotherapy, there was no change or a loss of<1.5% of body
weight within the first seven month after entry; those with
concurrent chemotherapy lost 4.8% and 5.2% (Table 3). Similarly,
the two CG patients (Patients 9 and 13, Table 2) who were treated
with chemotherapy lost more weight (17.7% and 16.4%, respectively)
than the average (11.6%). The average weight loss of the SVG
patients within the first seven months after entry was 2.1.+-.2.3%.
When the change in body weight between the two groups was compared,
p<0.01.
[0080] The TG patients either gained or had no change in their
weight measured 4-12 months after entry, with an average weight
gain of 4.0.+-.3.9%. The ineligible patient (Patient 12) showed no
weight change.
[0081] Performance Status
[0082] Within the first three months after entry, virtually all the
CG patients deteriorated rapidly, i.e., their KPS declined to
40-70, with an average of 55.4.+-.11.3 (p<0.01 compared with KPS
at entry) (Table 3). Except for one patient, the condition of the
SVG patients improved or remained the same, and their KPS was
60-90, with an average of 80.+-.13 (p>0.1 compared with KPS at
entry) (Table 4). The KPS of the CG and SVG patients after entry
were compared, yielding p<0.01.
[0083] Four of the SVG patients not receiving chemotherapy showed
an increase or no change in KPS. In the two patients treated with
concurrent chemotherapy, there was a decrease or no change in KPS
(Table 4). The condition of all TG patients and of the ineligible
patient (Patient 12) improved, and all were alive and well at 24
months, with KPS of 90.
4TABLE 3 Patient Characteristics: No Ingestion of SVS.sup.a KPS
Patient Stage: After BMI, % Wt Survival No. Age Gender Cell Type
TNM.sup.b Treatments At entry treatment.sup.c kg/m.sup.2
Change.sup.d mo 1 65 M Squamous IV: 3.2.1. R 80 60 (3) 27.1 -11.0
(7) 8 2 59 F Adenocarcinoma IV: 2.2.1. R 80 50 (3) 36.5 -3.7 (1) 5
3 54 M Squamous IV: 2.2.1. R 70 50 (3) 23.6 -13.2 (2) 4 4 45 M
Squamous IV: 1.3.1. R 80 50 (2) 28.0 -7.7 (3) 3 5 46 F
Undifferentiated IV: 2.1.1. S,R 70 40 (2) 22.9 NA 3 6 50 M Squamous
IIIB: 4.2.0. R 80 70 (1) 26.1 NA 1 7 56 F Poorly differentiated
IIIB: 3.3.0. R 80 60 (3) 31.2 -8.2 (1) 7 8 60 M Squamous IIIB:
4.0.0. S,R 70 40 (3) 26.6 NA 4 9 62 M Adenocarcinoma IIIB: 4.1.0. C
90 40 (2) 27.5 -17.4 (2) 4 10 65 M Squamous IIIA: 3.2.0. SC 90 70
(1) 21.1 NA 2 11 62 M Squamous IIIA: 3.1.0. R 70 60 (3) 22.5 -17.7
(3) 12 12 42 M Adenocarcinoma IIIA: 2.2.0. R 70 60 (1) 36.3 -8.7
(1) 2 13 40 F Adenocarcinoma IIIA: 3.2.0. C,R 90 70 (3) 19.5 -16.4
(3) 7 Mean .+-. 54.3 .+-. 78.5 .+-. 55.4 .+-. 26.7 .+-. -11.6 .+-.
4.8 .+-. SE 8.8 8.0 11.3 5.5 4.9 3.0 a: Abbreviations are as
follows: SVs, selected vegetables; M, male; F, female; R,
radiotherapy; C, chemotherapy; s, surgery; SC, supportive care
without R, S, or C; NA, not available; KPS, Karnofsky performance
scale; BMI, body mass index. b: Intemational staging system for
lung cancer. c: Months after treatment in parentheses. d:
Percentage of weight lost between first and later visit, with
months between measurements in parentheses; weight measured at
first visit was used as denominator.
[0084]
5TABLE 4 Patient Characteristics: Who Ingestion of SVS.sup.a KPS
Patient Stage and After BMI, % Wt Survival, No. Age Gender Cell
Type TNM.sup.b Treatments At entry treatment.sup.c kg/m.sup.2
Change.sup.d SV mo mo Stage III and IV patients for survival study
1 50 M Squamous IV: 2.2.1. R 70 90 (3) 26.1 -1.2 (5) 7 >24 2 49
M Squamous IV: 2.1.1. R 70 80 (3) 30.7 0.0 (5) 5 16 3 52 M
Adenocarcinoma IIIB: 4.1.0. R 80 90 (3) 24.0 -1.3 (7) 17 18 4 55 M
Squamous IIIB: 2.3.0. C 70 70 (3) 29.4 -4.8 (6) 4 9 5 41 F
Adenocarcinoma IIIB: 4.3.0. C 70 60 (3) 27.3 -5.2 (3) 7 8 6 48 M
Adenocarcinoma IIIA: 2.2.0. R 90 90 (3) 24.1 0.0 (3) 4 15 Mean .+-.
49.2 .+-. 75 .+-. 80 .+-. 27.0 .+-. -2.1 .+-. SE 4.7 8.4 13 2.7 2.3
Stage I patients for toxicity study 7.sup.e 41 M Squamous I: 2.0.0.
S,R 70 90 (3) 24.1 2.3 (12) >24 >24 8 63 M Squamous I: 1.0.0.
R 90 90 (3) 26.7 0.0 (5) >17 >24 9 68 M Squamous I: 1.0.0. R
80 90 (3) 27.7 7.5 (7) >20 >24 10 55 M Large cell I: 2.0.0. R
70 90 (3) 22.2 8.8 (8) >20 >24 11 46 M Squamous I: 2.0.0. R
80 90 (3) 22.6 1.3 (4) >18 >24 Mean .+-. 54.6 .+-. 78.0 .+-.
90.0 .+-. 24.7 .+-. 4.0 .+-. SE 11.3 8.4 0.0 2.4 3.9 Ineligible
patient 12.sup.f 47 F Adenocarcinoma N/A S,C,R 70 90 (3) 31.2 1.2
>24 >24 a: See Table 2 footnote for definition of
abbreviations. b: International staging system for lung cancer. c:
Months after treatment in parentheses. d: Percentage of weight lost
between first and later visit, with months between measurements in
parentheses; weight measured at first visit was used as
denominator. e: Patient 7 had lesions in both adrenal glands, but
no biopsy was performed. f: Patient 12 had colon cancer in 1983 and
was excluded from analyses. Her lung tumor was presumed to be
metastatic colon cancer. N/A, not applicable.
[0085] Survival Time
[0086] The CG patients survived from 1 to 12 months, and all died
before the cutoff date, with an average survival time of 4.8.+-.3.0
months (Table 3). The median survival time was four months with a
95% confidence interval of three to seven months (FIG. 5). If the
worst survivors (Patients 6, 10 and 12) were excluded from
evaluation, the remaining patients survived for 3-12 months, and
the median survival time was 4.5 months, with a 95% confidence
interval of 4-7 months, with an average survival time of 5.7.+-.3.0
months.
[0087] SVG patients ingested SV for 4-17 months. The median
survival time was 15.5 months, and its 95% confidence interval was
9-18 months, and one patient survived >24 months (FIG. 5). In
the log-rank test comparing median survival times of the SVG and
the CG patients (including or excluding Patients 6, 10, and 12),
p<0.01, indicating that the median survival time of the SVG
patients is significantly longer than that of the CG patients.
Thus, H.sub.0 is not supported by the data and rejected, but H2 is
supported and accepted. If Patient 1 was assumed to be dead at the
cutoff date (Table 4), the Wilcoxon Rank and Sum test for small
sample size could then be used. The mean survival times of the SVG
and the CG patients were 15 and 4.8 months (or 5.7 months excluding
the worst survivors), respectively, with p<0.01, indicating that
the former is significantly longer than the latter. Again H.sub.0
is not supported by the data and rejected, but H.sub.2 is supported
and accepted.
[0088] One patient (Patient 7) had lesions in both adrenal glands,
but no biopsy was performed. He was classified as stage I for
toxicity evaluation only. One other patient (Patient 12) had colon
cancer in 1983 and was presumed to have metastatic colon cancer on
review. Both patients were alive and well beyond 24 months, but
they were not included in survival analyses.
[0089] Toxicity Evaluation of Patients Ingesting SV
[0090] All patients who ingested SV (Table 4) showed no clinical
signs of toxicity (see Materials and Methods). Their blood
chemistry data indicated that no significant hematologic, renal, or
hepatic toxicity occurred. The five stage I TG patients ingested SV
daily for 17-24 months (Table 4). All were treated with
radiotherapy and/or surgery, but not chemotherapy. None of these
patients showed weight loss, bleeding, or any clinical symptoms of
gastrointestinal, neurological, or cardiopulmonary dysfunction. All
were alive and well with stable tumor at the end of the 24-month
study period. They maintained or resumed routine activities,
including daily full-time work, exercise, and sexual activity. No
clinical signs of toxicity were detected. None developed new tumor
during the study period. Some patients reported a feeling of
fullness or bloatedness after ingesting SV, and some found it
difficult to consume 30 g of SV daily. A few patients did not care
for the taste of SV. Nonetheless, all five TG patients ingested SV
daily for >17 months.
Discussion
[0091] This exploratory study tests the hypothesis that the daily
ingestion of a combination of foods that contain different types of
antitumor components may benefit patients with stage III and IV
NSCLC. Several vegetables contain molecularly defined components
with immune-modulating or antitumor activity (Table 1). The
individual activities, although well documented, have only modest
potencies. They have different mechanisms of action and thus may
act synergistically when used together. These antitumor entities
are not toxic. Adding them to the daily diet of cancer patients
incurs minimal risk.
[0092] Conventional therapies afford only marginal benefit for
stage IIIB and IV NSCLC. The median survival time of stage IIIB and
IV NSCLC patients is usually short. Thus, adding a dietary
supplement to the patients' daily diet without interfering with
conventional therapies was deemed ethical, and adequate clinical
observation could be achieved within 24 months.
[0093] The number of SVG patients is small, but the difference in
median survival times between CG and SVG patients is large
(3-fold). The Log-Rank test showed p<0.01 and no overlap in the
95% confidence intervals of the two median survival times,
indicating a significant difference between SVG and CG patients.
Furthermore, using the Wilcoxon Rank Sum test, which could also be
used to compare groups of small sample size, the mean survival time
of the SVG patients is also statistically longer than that of CG
patients (p<0.01). Moreover, using even more conservative
evaluation, if the CG patients with the shortest survivals
(Patients 6, 10, and 12) are excluded from analysis, the median
survival time and mean survival time of CG patients are still
significantly different from those of SVG patients (p<0.01).
[0094] Most patients failed to ingest SV for the intended period,
but all patients ingested SV for four months or longer. Failure to
ingest SV for the intended period was mostly due to lack of
motivation and confidence in the efficacy of SV, boredom and
monotony in taking 30 g of SV powder daily, taste preference of
patients unaccustomed to high-fiber, low-fat foods, bloating,
fullness, and cancer-related anorexia. SVG patients (stage III-IV),
except for Patient 3, discontinued SV ingestion earlier than TG
patients (stage I), possibly because they were weaker or more
sensitive to one or more of the factors listed above. No attempt
was made to rank the importance of these factors. Because no prior
data on efficacy of using SV for different durations were
available, all these patients were included in analyses to avoid
bias.
[0095] Nonrandomized trials are recommended for phase II studies.
Bias in patient selection can be minimized by using the same
clinical entry criteria and prognostic factors for patients in the
control and the study group. In the present study, tumor cell type,
stage, previous and concurrent therapies, age, gender, KPS, and BMI
in the CG and the SVG patients were comparable. KPS, change in body
weight, and extent of disease are considered strong survival
predictors for cancer patients. These prognostic indicators were
comparable in the CG and the SVG patients at entry but rapidly
declined in the CG patients. In contrast, they often improved or
remained unchanged, or their decline was less rapid and severe in
SVG patients. All these indicators improved or were unchanged in
all TG patients. Thus, ingestion of SV was associated with
maintenance or improvement in KPS and body weight.
[0096] The median survival time of the CG patients was within the
expected historical range. Median survival time and mean survival
were significantly longer for SVG than for CG patients. For changes
of KPS and body weight, each patient was used as his own control.
These changes within individual patients are not affected by the
difference between patients or by the number of patients and are
strong prognostic indicators for patient survival. The rapid
declines in these survival indicators in the CG but not in the SVG
patients are consistent with the observed survival difference
between the two groups.
[0097] Quality of life and avoidance of drug toxicity, cachexia,
and recurrent and metastatic disease remain important challenges in
the treatment of NSCLC. In the 24-month study period, no detectable
toxicity occurred in the five stage I patients, and their KPS and
body weight also improved. Moreover, although recurrent tumor in
stage I NSCLC patients is a major cause of death, all five stage I
TG patients had no recurrent tumor in the two-year study period.
They all had primary radiotherapy, and one also had surgery. Their
24-month recurrence-free survival compares favorably with the 59%
recurrence rate and the 52% death rate due to lung cancer in two
years for stage I NSCLC patients treated with radiotherapy alone or
the 35% two-year recurrence rate of stage I NSCLC patients treated
with surgery alone.
[0098] The apparent benefit of SV may be due to one or more
antitumor components in SV (Table 1). The antitumor effect of
purified forms of .beta.-glucans has been well documented and is
host mediated. Soybeans contain various antitumor components, e.g.,
protease inhibitors, saponins, inositol hexaphosphate, genistein,
and other phytoestrogens. Moreover, NSCLC is an immune-suppressing
disease, and immunosuppressive factors produced by NSCLC cells have
been well characterized. Further investigations of the benefits of
SV and other combinations of foods containing different antitumor
and immune-enhancing entities for cancer patients are warranted.
This approach is attractive because of its simplicity, low cost,
and lack of toxicity.
[0099] This study indicates that the daily ingestion of SV is safe,
nontoxic, and well tolerated by NSCLC patient at all stages. The
prolonged survival of stage III/IV NSCLC patients observed in this
phase I/II study is noteworthy and warrants further large,
placebo-controlled, randomized studies. Given the high incidence
and poor prognosis of lung cancer, modest improvements in survival
can be translated into many thousands of useful added years for
NSCLC patients.
[0100] Furthermore, strong Antitumor efficacy of SV was also
observed in 2 tumor models in mice, namely, lung carcinoma Line I
in BALB/c mice and Sarcoma S1509a in A/J(H-2a) mice (2,3).
Example 2
Colon Cancer
[0101] Subsequently, a Czech patient with stage IV colon cancer had
an unusually prolonged survival (>4 years) with conventional
therapies and daily ingestion of SV.
[0102] Four sets of CT scans were taken on the following dates:
Oct. 13, 1986, Nov. 11, 1986, Nov. 26, 1986, and Feb. 10, 1987.
Three intracranial enhancing lesions (FIGS. 2A, 2B, and 2C) were
identified; their transverse directions were measured (in mm).
[0103] In FIG. 2A, the lesion, located in the left posterio-lateral
middle frontal gyrus, was surrounded by edema anteriorly and
medially. No obvious focal indentation, deformity, or shift of the
ventricular system was observed. The lesion measured 13 mm (Al);
13.6 m (A2); 8.6 mm (A3); no clear cut enhancing mass lesion was
identified in the area (A4). The edema represented by areas of low
density shows marked diminution. Unlike the first, second, and
third CT scans, where the lesions are still clearly seen, the last
CT scan was taken with a higher quality scanner (GE 9800 scanner).
Therefore, even a small enhancing lesion, if still present, should
be better demonstrated.
[0104] In FIG. 2B, the lesion, located in the medial aspect of the
precentral gyrus on the left side immediately adjacent to the falx,
measured 7.7 mm (B1); 11.5 mm (B2); 6.7 mm (B3); no clear cut
enhancing mass lesion was identified in the area (B4).
[0105] In FIG. 2C, the lesion was located in the precentral gyrus
(upper convexity side). A moderate degree of edema was seen
involving the white matter of the high frontoparietal lobe. The
pre- and postcentral gyri were widened and the adjacent sulci were
narrowed. This lesion measured 11.5 mm (C1); 12.1 mm (C2); 6.0 mm
(C3); no clear cut enhancing mass lesion was identified in the area
(C4).
Example 3
AIDS Treatment
[0106] An AIDS patient was administered SV when his CD4.sup.+
decreased to a dangerously low level (95 cells/mm.sup.3) condition
deteriorated, and had multiple infections. After ingesting SV for 2
months, not only his health improved to normal level, his CD4.sup.+
cell count also increased to normal level, namely, to 475 in 2
months and over 600 in 6 months. This patient did not receive any
other treatment except for daily ingestion of SV during this time.
Thus, the change in his CD4.sup.+ cell count and health condition
after ingesting SV alone is considered an objective response to
SV.
* * * * *