|Alternative Medicine Cancer Fact Sheet:
Cartilage (Bovine and Shark)
Levels Of Evidence
Glossary Of Terms
For More Information
This complementary and
alternative medicine (CAM) information summary provides an overview of the
use of cartilage as a treatment for cancer. The
summary includes a brief history of cartilage
research, the results of clinical studies, and
possible side effects of cartilage use. A glossary
of scientific terms used in the summary appears just before the references.
Terms defined in the glossary are marked in the text by hypertext links.
This summary contains the following key information:
- Bovine (cow) cartilage and shark cartilage have been studied as treatments for cancer and
other medical conditions for more than 30 years.
- Numerous cartilage products are sold
commercially in the United States as dietary supplements.
- Three principal mechanisms of action have been proposed to explain the
antitumor potential of cartilage: 1) it kills cancer
cells directly; 2) it stimulates the immune system; 3) it blocks the formation
of new blood vessels (angiogenesis), which tumors
need for unrestricted growth.
- At least three different inhibitors of angiogenesis have been identified in bovine cartilage, and two
angiogenesis inhibitors have been
purified from shark cartilage.
- Only three human studies have been published to date, and the results
are inconclusive about the effectiveness of cartilage
as a treatment for cancer.
- Additional clinical trials of cartilage as a treatment for cancer are now being
Bovine cartilage and shark cartilage have been investigated as treatments for
cancer, psoriasis, arthritis, and a number of other medical conditions for
more than 30 years.[1-13, reviewed in 14-21] At least some of the interest in
cartilage as a treatment for cancer arose from the
mistaken belief that sharks, whose skeletons are made
primarily of cartilage, are not affected by this
disease.[reviewed in 17,22] Although reports of malignant tumors in sharks are rare, a variety of
cancers have been detected in these animals.[reviewed in 22-24] Nonetheless,
several substances that have antitumor activity have been identified in cartilage.[25-48, reviewed in 2-4,6-10,16-21,49,50]
More than a dozen clinical studies of cartilage as a treatment for cancer have already been
conducted, [2-4,10-13, reviewed in 6-9,15-20] and additional clinical studies are now under way.[51,52, reviewed
The absence of blood vessels in cartilage led to
the hypothesis that cartilage cells (also known as chondrocytes) produce one or more substances that
inhibit blood vessel formation.[reviewed in 28-31,36,37,50] The formation of
new blood vessels, or angiogenesis, is necessary
for tumors to grow larger than a few millimeters in
diameter (i.e., larger than approximately 100,000 to
1,000,000 cells) because tumors, like normal tissues, must obtain most of
their oxygen and nutrients from blood.[reviewed in 34,35,42,53-56] A
developing tumor, therefore, cannot continue to grow unless it establishes
connections to the circulatory system of its
host. It has been reported that tumors can initiate the process of angiogenesis when they contain as few as 100
cells. Inhibition of angiogenesis at this
early stage may, in some instances, lead to complete tumor regression. The possibility that cartilage could be a source of one or more types of angiogenesis inhibitors for the treatment
of cancer has prompted much research.
The major structural components of cartilage
include several types of the protein collagen and
several types of glycosaminoglycans, which
are polysaccharides.[reviewed in
21,30,31,40,50,56,57] Chondroitin sulfate
is the major glycosaminoglycan in cartilage.[reviewed in 40,56] Although there is no
evidence that the collagens in cartilage, or their breakdown products, can inhibit angiogenesis, there is evidence that shark cartilage contains at least one
angiogenesis inhibitor that has a glycosaminoglycan component (see Laboratory/Animal/Preclinical Studies section). Other data
indicate that most of the antiangiogenic
activity in cartilage is not associated with the
major structural components. [reviewed in 27,31,50]
Some glycosaminoglycans in cartilage reportedly have
anti-inflammatory and immune
system-stimulating properties,[58,59, reviewed in 1,2,14,17] and it has been
suggested that either they or some of their breakdown products are toxic to
tumor cells.[25, reviewed in 2,3] Thus, the antitumor potential of cartilage may involve more than one mechanism of
Cartilage products are sold commercially in the
United States as dietary supplements. More than 40 different brand names of
shark cartilage alone are available to
consumers.[reviewed in 19] In the United States, dietary supplements are
regulated as foods, not drugs. Therefore, premarket evaluation and approval
by the Food and Drug Administration (FDA) are not required unless specific
disease prevention or treatment claims are made. Because manufacturers of cartilage products are not required to show evidence of
anticancer or other biologic effects,[reviewed in 19] it is unclear whether
any of these products has therapeutic potential.
In addition, individual products may vary considerably from lot to lot because
standard manufacturing processes do not exist and
binding agents and fillers
may be added during production.[reviewed in 19]
To conduct clinical drug research in the United States, researchers must
file an Investigational New Drug (IND) application with the FDA. To date, IND
status has been granted to at least four groups of investigators to study cartilage as a treatment for cancer.[10,51,52,60,
reviewed in 20] Because the IND application process is confidential and
because the existence of an IND can be disclosed only by the applicants, it is
not known whether other applications have been made.
In animal studies, cartilage products have been
administered in a variety of ways. In some studies, oral
administration of either liquid or powdered forms has been used.[21,40,41,44-
46,61, reviewed in 7-9,16,49] In other studies, cartilage products have been given by injection (intravenous or intraperitoneal), applied topically, or placed in slow-release, plastic pellets that
were surgically implanted.[27,28,33,34,36,39,41,43, reviewed in 29,48,50]
Most of the latter studies investigated the effects of cartilage products on the development of blood vessels
in the chorioallantoic membrane of
chicken embryos, the cornea of
rabbits, or the conjunctiva of
mice.[27,28,33,36,39,41,43, reviewed in 29,48,50]
In human studies, cartilage products have been
administered topically or orally,
or they have been given by enema or subcutaneous injection.[2-4,6,10-13,51,52, reviewed
in 7-9,15-18,20] For oral administration, liquid,
powdered, and pill forms have been used.[2-4,6,10-13,51,52, reviewed in 7-
9,15-18,20] The dose and duration of cartilage
treatment have varied in human studies, in part because different types of
products have been tested.
In this summary, the brand name (i.e., registered or trademarked name) of
the cartilage product(s) used in individual studies
will be identified wherever possible.
The therapeutic potential of cartilage has been investigated for more than 30 years.
As noted previously (General Information section), cartilage products have been tested as treatments for
cancer, psoriasis, and arthritis. Cartilage products
have also been studied as enhancers of wound repair and as treatments for osteoporosis,
regional enteritis, acne, scleroderma, hemorrhoids, severe anal itching,
and the dermatitis caused by poison oak and poison
ivy.[59, reviewed in 1,14,17,21]
Early studies of cartilage's therapeutic potential used extracts of bovine cartilage. The ability of these extracts to suppress inflammation was first described in the early
1960s. The first report that bovine cartilage
contains at least one
angiogenesis inhibitor was published in
the mid-1970s. The use of bovine cartilage
extracts to treat patients with cancer and the ability of these extracts to
kill cancer cells directly and to stimulate animal immune systems were first
described in the mid- to late-1980s.[2,3,25,58]
In contrast, the first report that shark cartilage
contains at least one angiogenesis
inhibitor was published in the early 1980s, and the only published
report to date of a clinical trial of shark cartilage as a treatment for cancer appeared in the late
1990s. The more recent interest in shark cartilage is due, in part, to the greater abundance of
cartilage in this animal and its apparently higher
level of antiangiogenic activity. It has been
estimated that 6% of the body weight of a shark is composed of cartilage, compared with less than 1% of the body weight
of a cow.[reviewed in 20] In addition, it has been estimated that, on a
weight-for-weight basis, shark cartilage contains
1,000 times more antiangiogenic activity than
bovine cartilage.[39, reviewed in 18]
As indicated previously (Overview and
General Information sections), at least three different
mechanisms of action have been proposed to explain the anticancer potential of
cartilage: 1) it is toxic to cancer cells; 2) it
stimulates the immune system; and 3) it inhibits angiogenesis. There is only limited evidence to
support the first two mechanisms of action; however, the evidence in favor of
the third mechanism is more substantial (see Laboratory/Animal/Preclinical Studies section).
The process of angiogenesis requires at least
four coordinated steps, each of which may be a target for inhibition. First,
tumors must communicate with the
endothelial cells that line the inside of
nearby blood vessels. This communication takes place, in part, through the
secretion of angiogenesis factors, such as
vascular endothelial growth factor (VEGF).[reviewed in 53-56,62] Second,
the "activated" endothelial cells must divide
to produce new endothelial cells, which will
be used to make the new blood vessels.[reviewed in 54,56,62-64] Third, the
dividing endothelial cells must migrate toward
the tumor.[reviewed in 54-56,62-64] To accomplish this, they must produce enzymes called
matrix metalloproteinases, which will
help them carve a pathway through the tissue elements that separate them from
the tumor.[reviewed in 62-65] Fourth, the new endothelial cells must form the hollow tubes that will become the
new blood vessels.[reviewed in 56,62] It is conceivable that some angiogenesis inhibitors may be able to
block more than one step in this process.
It is important to note that cartilage is
relatively resistant to invasion by tumor cells [reviewed in
30-32,35,36,38,48,50] and that tumor cells use
matrix metalloproteinases when they
migrate during the process of metastasis.[reviewed
in 18,26,32,49,65] Therefore, if the
angiogenesis inhibitors in cartilage are also inhibitors of
matrix metalloproteinases, then the
same molecules may be able to block both angiogenesis and metastasis. It should also be noted that shark tissues
other than cartilage have been reported to produce
antitumor substances.[66-68, reviewed in 69]
The antitumor potential of cartilage has been
investigated extensively in laboratory and animal studies. Some of these
studies have focused on the toxicity of cartilage
products toward cancer cells in vitro.[25,42, reviewed
In one study, cells from 22 freshly isolated human tumors (nine ovary,
three lung, two brain, two breast, and one each of sarcoma, melanoma, colon, pancreas, cervix, and testis) and
three human cultured cell lines (breast
cancer, colon cancer, and myeloma) were treated with
Catrix®, which is a commercially available powdered preparation of bovine
cartilage.[25, reviewed in 2,3,18] In the study, the
growth of all three cultured cell lines and
of cells from approximately 70% of the tumor specimens was inhibited by 50% or
more when Catrix® was used at high concentrations (1 to 5 milligrams per milliliter of
culture fluid). It is unclear, however, whether the inhibitory effect of
Catrix® in this study was specific to the growth of cancer cells because
its effect on the growth of normal cells was not tested. In addition, the
"toxic" component of Catrix® has not been identified, and it has not been
shown that equivalent inhibitory concentrations of this component can be
achieved in the bloodstream of patients who may be treated with either
injected or oral formulations of this product. (See Human/Clinical Studies section for a discussion of human studies
A liquid (i.e., aqueous) extract of shark cartilage, called AE-941/Neovastat®, has also been
reported to inhibit the growth of a variety of cancer cell types
in vitro.[reviewed in 16,45] However, these results
have not been published in a peer-reviewed, scientific journal.
In contrast, a commercially available preparation of powdered shark cartilage (no brand name given) was reported to have no
effect on the growth of human astrocytoma cells in vitro. In this published study, the shark cartilage product was tested at only one concentration
(0.75 milligrams per milliliter).
The immune system-stimulating potential of cartilage has also been investigated in laboratory and
animal studies, but just one study has been published in the peer-reviewed,
scientific literature. In that study, Catrix® was shown to stimulate
the production of antibodies by mouse
B cells (B lymphocytes) both
in vitro and in vivo. However,
increased antibody production
in vivo was observed only when Catrix® was given
by intraperitoneal or intravenous injection. It was not observed when oral formulations of Catrix® were used. It is
important to note that, in most experiments, the proliferation of mouse B cells (i.e., normal, nonmalignant cells) in vitro
was increasingly inhibited as the concentration of Catrix® was increased
(tested concentration range: 1 to 20
milligrams per milliliter).
Catrix® has also been reported to stimulate the activity of mouse macrophages in vivo, [reviewed
in 2,18] but results demonstrating this effect have not been published in a
peer-reviewed, scientific journal. To date, no studies of the immune
system-stimulating potential of shark cartilage have
A large number of laboratory and animal studies have been published
concerning the antiangiogenic potential of
cartilage.[5,26-31,33-37,39-43] Overall, these
studies have revealed the presence of at least three
angiogenesis inhibitors in bovine cartilage [26,27,30,31,35,37, reviewed in 29,50] and, in
shark cartilage, of at least two.[41-43,48]
Three angiogenesis inhibitors in
bovine cartilage have been very well
characterized.[26,27,30,31,35,37, reviewed in 29,50] They are relatively
small proteins with molecular masses that range
from 23,000 to 28,000.[26,27,37, reviewed in 29] These proteins, called cartilage-derived inhibitor (CDI), cartilage-derived antitumor factor (CATF), and cartilage-derived collagenase
inhibitor (CDCI) by the researchers who purified them,[26,27,35] have been
shown to block endothelial cell proliferation
in vitro and new blood vessel formation in the chorioallantoic membrane of chicken
embryos.[27,30,31,35,37, reviewed in 29,50] Two of the proteins (CDI and
CDCI) have been shown to inhibit
matrix metalloproteinase activity in vitro,[26,27,31, reviewed in 29] and one (CDI) has
been shown to inhibit
endothelial cell migration
in vitro.[27, reviewed in 29] These proteins do not
block the proliferation of normal cells or of tumor cells
in vitro.[27,30,35, reviewed in 29,50] When the amino acid sequences of CDI, CATF, and CDCI
were determined, it was discovered that they were the same as those of
proteins known otherwise as TIMP-1 (tissue inhibitor of
matrix metalloproteinases 1), ChMI
(chondromodulin I), and TIMP-2 (tissue inhibitor of
matrix metalloproteinases 2),
respectively.[26,27,31,37, reviewed in 50]
A possible fourth angiogenesis
inhibitor in bovine cartilage has been purified
not from cartilage but from the culture fluid of
bovine chondrocytes grown in the laboratory.
This inhibitor, which has been named
chondrocyte-derived inhibitor (ChDI), is a protein
that has a molecular mass of approximately
36,000. It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[28, reviewed in 29,50]
but the relationship between these proteins is unclear because
amino acid sequence information for ChDI is
not available. Thus, whether CDI/TIMP-1 is a breakdown product of ChDI or
whether ChDI is truly the fourth
angiogenesis inhibitor identified in
bovine cartilage is unknown.
As indicated previously, shark cartilage, like
bovine cartilage, contains more than one type of angiogenesis inhibitor. One shark cartilage inhibitor, named U-995, reportedly contains
two small proteins, one with a molecular mass of
approximately 14,000 and the other with a
molecular mass of approximately 10,000.
Both proteins have shown antiangiogenic activity
when tested individually. The exact relationship between these two
proteins, as well as their relationship to the larger bovine angiogenesis inhibitors, is not known
because amino acid sequence information for
U-995 is not available. U-995 has been reported to inhibit endothelial cell proliferation, endothelial cell migration, and
matrix metalloproteinase activity in vitro and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos. It does not appear to inhibit the
proliferation of other types of normal cells or of cancer cells
in vitro. Intraperitoneal, but not oral,
administration of U-995 has been shown to inhibit the growth of mouse sarcoma-180 tumors implanted subcutaneously on the backs of mice and the formation
of lung metastases of mouse B16-F10 melanoma cells
injected into the tail veins of mice.
The second angiogenesis inhibitor
identified in shark cartilage appears to have been
studied independently by three groups of investigators.[42,43,48] This
inhibitor, which was named SCF2 by one of the groups, is a proteoglycan that has a
molecular mass of less than 10,000. Proteoglycans are combinations of glycosaminoglycans and protein.[reviewed in 56]
The principal glycosaminoglycan in SCF2 is keratan sulfate. SCF2 has been shown to block
endothelial cell proliferation
in vitro,[42,43,48] the formation of new blood vessels
in the chorioallantoic membrane of
chicken embryos,[42,43] and tumor-induced angiogenesis in the cornea of
Other studies have indicated that AE-941/Neovastat®, the previously
mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[5, reviewed in 45] but the
molecular basis for this activity has not been
defined. Therefore, whether AE-941/Neovastat® contains U-995 and/or SCF2
or some other angiogenesis inhibitor is
not known. It has been reported that AE-941/Neovastat® inhibits endothelial cell proliferation and matrix metalloproteinase activity in vitro and the formation of new blood vessels in the chorioallantoic membrane of chicken
embryos.[5, reviewed in 45] It may also inhibit the
vascular endothelial growth factor (VEGF), thus interfering with the
communication between tumor cells and nearby blood vessels.
AE-941/Neovastat® has also been reported to inhibit the growth of DA3
mammary adenocarcinoma cells and the metastasis of Lewis lung carcinoma cells in vivo in
mice.[45,46, reviewed in 8,9,16,49] In the Lewis lung carcinoma experiments, AE-941/Neovastat® reportedly
enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[46, reviewed in 8,9,16,49] It is important
to note, however, that most of the results obtained with
AE-941/Neovastat® have not been published in peer-reviewed, scientific
Additional in vivo studies of the antitumor
potential of shark cartilage have been published in
the peer-reviewed, scientific literature.[40,44,61] In one study, oral administration of powdered shark cartilage (no brand name given) was shown to inhibit
chemically induced angiogenesis in the mesenteric membrane of rats. In another
study, oral administration of powdered shark cartilage (no brand name given) was shown to reduce the
growth of GS-9L gliosarcomas in rats. In
contrast, it was reported in a third study that oral
administration of two powdered shark cartilage
products, Sharkilage® and MIA Shark Powder, did not inhibit the growth or
the metastasis of SCCVII
squamous cell carcinomas in
More than a dozen clinical studies of cartilage as a treatment for cancer have been conducted
since the early 1970s.[2-4,10-13, reviewed in 6-9,15-20] However, results
from only three studies have been published in peer-reviewed, scientific
journals.[2,3,10] Although additional
clinical studies are now under way,[51,52,
reviewed in 9,16] the cumulative evidence to date is inconclusive regarding
the effectiveness of cartilage as a cancer treatment
Two of the three published clinical studies
evaluated the use of Catrix®, the previously mentioned (Laboratory/Animal/Preclinical Studies section) powdered
preparation of bovine cartilage, as a treatment for
various solid tumors.[2,3] One of these studies was a
case series that included 31 patients; the other
was a phase II clinical trial that included nine
In the case series, all patients were treated
with subcutaneously injected and/or oral Catrix®; however, three patients (one with squamous cell carcinoma of the skin and
two with basal cell carcinoma of the skin)
were treated with topical preparations as well. The
individual dose, the total dose, and the duration of Catrix® treatment in
this series varied from patient to patient; however, the minimum treatment
duration was 7 months, and the maximum duration was more than 10 years.
Eighteen patients had been treated with
conventional therapy (surgery, chemotherapy,
hormone therapy) within 1 year of the start of
Catrix® treatment; nine patients received
conventional therapy concurrently (at the
same time) with Catrix® treatment; and seven patients received conventional therapy both prior to and during
Catrix® treatment. It was reported that 19 patients had a complete response, 10 patients had a partial response, and one patient had stable disease following Catrix® treatment.
The remaining patient did not respond to cartilage
therapy. Eight of the patients with a
complete response received no prior or
concurrent conventional therapy.
Approximately half of the patients with a
complete response eventually experienced
This clinical study had several weaknesses that
could have affected its outcome, including the absence of a
control group and the receipt of prior and/or
concurrent conventional therapy by the
majority of patients.
In the phase II trial, Catrix® was
administered by subcutaneous injection only. All
patients in this trial had
progressive disease following radiation therapy and/or chemotherapy. Identical individual doses of
Catrix® were given to each patient, but the duration of treatment and the
total delivered dose varied because of disease progression or death. The
minimum duration of Catrix® treatment in this study was 4 weeks. It was
reported that one patient (with metastatic renal cell carcinoma) had a
complete response that lasted more than 39
weeks. The remaining eight patients did not respond to Catrix®
treatment. The researchers in this trial also investigated whether
Catrix® had an effect on immune system function in these patients. No
consistent trend or change in the numbers, percentages, or ratios of white blood cells (i.e., total lymphocyte counts, total T cell
counts, total B cell counts, percentage of
T cells, percentage of B cells,
ratio of helper T cells to cytotoxic T cells) was observed,
although increased numbers of T cells were found in
Partial results of a third clinical study of
Catrix® are described in an abstract submitted for presentation at a
scientific conference, but complete results of this study have not been
published in a peer-reviewed, scientific journal. In the study, 35 patients
renal cell carcinoma were divided into four
groups, and the individuals in each group were treated with identical doses of
subcutaneously injected and/or oral Catrix®. Three
partial responses and no
complete responses were observed among 22 evaluable patients who were treated with
Catrix® for more than 3 months. Two of the 22
evaluable patients were reported to have stable disease and 17 were reported to have progressive disease following Catrix®
therapy. No relationship could be established between Catrix® dose and
tumor response in this study.
The third published study of cartilage as a
treatment for cancer was a phase I/II trial
that tested the safety and the efficacy of orally
administered Cartilade®, a commercially available powdered preparation of
shark cartilage, in 60 patients with various types of
advanced solid tumors. All but one patient in this trial had been treated
previously with conventional therapy.
According to the design of the study, no additional anticancer treatment could
be given concurrently with Cartilade® therapy. No
complete responses or
partial responses were observed among 50 evaluable patients who were treated with
Cartilade® for at least 6 weeks. However,
stable disease that lasted 12 weeks or more was
reported for 10 of the 50 patients. All 10 of these patients eventually
experienced progressive disease.
Partial results of three other
clinical studies of powdered shark cartilage are described in two abstracts submitted for
presentation at scientific conferences,[11,12] but complete results of these
studies have not been published in
peer-reviewed, scientific journals. All three studies were
phase II clinical trials that involved patients
with advanced disease; two of the studies were conducted by the same group of
investigators. These three studies enrolled 20 patients with breast
cancer, 12 patients with prostate cancer, and 12 patients with primary
brain tumors. All patients had been treated previously with conventional therapy. No other anticancer
treatment was allowed concurrently with cartilage
therapy. In two of the studies, the name of the cartilage product was not identified; however, in the
third study, the commercially available product BeneFin® was used.
Ten patients in each study completed at least 8 weeks of treatment and were,
therefore, considered evaluable for response. No complete responses or
partial responses were observed in any of the
studies. Two patients in each study were reported to have
stable disease that lasted 8 weeks or more.
The safety and the efficacy of AE-941/Neovastat®, the previously
mentioned aqueous extract of shark cartilage, have also been examined in
clinical studies.[6-9, reviewed in 15,16]
However, results of these studies have been described only in abstracts
presented at scientific conferences and in press releases by the manufacturer
and not in peer-reviewed, scientific journals.
The exact number of clinical studies of
AE-941/Neovastat® is difficult to determine because of inconsistencies in
the information that is available. It appears that at least two clinical studies have been conducted: 1) a phase I/II trial of oral
AE-941/Neovastat® as a single agent in 80 patients with advanced lung
cancer and 72 patients with advanced prostate cancer, and 2) a study of oral AE-941/Neovastat® plus chemotherapy and/or
radiation therapy in 126 patients with
various types of solid tumors.[7-9,15,16] The
phase I/II trial has been variously described
as a single phase I/II study,[7-9,16] two phase I studies,[15,16], two
phase II studies, a study that involved only
patients with advanced lung cancer,[7,8,16] and a study that involved both
patients with advanced lung cancer and patients with advanced prostate
It has been reported that AE-941/Neovastat® has little
toxicity,[6-9,15,16,45,46] and there are indications from a retrospective analysis of data from the phase I/II trial that it may have anticancer
activity in humans. In addition, there is evidence from a randomized clinical trial that examined
the effect of AE-941/Neovastat® on the angiogenesis associated with surgical wound repair
that this extract contains at least one antiangiogenic component that is orally bioavailable.
On the basis of laboratory, animal, and human data provided by the
manufacturer, two randomized
phase III trials of AE-941/Neovastat® in
patients with advanced cancer have been approved by the FDA. In one trial,
treatment with oral AE-941/Neovastat® plus chemotherapy and
radiation therapy is being compared to
treatment with placebo plus the same chemotherapy
and radiation therapy in patients with
stage III non-small cell lung cancer. In the other trial, treatment
with oral AE-941/Neovastat ® is being compared to
treatment with placebo in patients with metastatic
renal cell carcinoma. Both trials are
currently enrolling patients.
The side effects associated with cartilage therapy
are generally described as mild-to-moderate in severity. Inflammation at injection sites, dysgeusia, fatigue, nausea, dyspepsia, fever, dizziness, and edema of the scrotum have been
reported after treatment with the bovine cartilage
product Catrix®.[2-4] Nausea, vomiting, abdominal cramping and/or bloating, constipation, hypotension, hyperglycemia, generalized weakness, and hypercalcemia have been associated with the use of
powdered shark cartilage.[10-12] The high level of
calcium in shark cartilage may contribute to the
development of hypercalcemia.[11,18] In
addition, one case of hepatitis has been associated
with the use of powdered shark cartilage. Nausea
and vomiting are the most commonly reported side effects following treatment
with AE-941/Neovastat ®, the aqueous extract of
Levels of Evidence for Human Studies of Cancer
Complementary and Alternative Medicine
To assist readers in evaluating the results of human studies of CAM
treatments for cancer, the strength of the evidence (i.e., the "levels of
evidence") associated with each type of treatment is provided whenever
possible. To qualify for a levels of evidence analysis, a study must 1) be
published in a peer-reviewed, scientific journal; 2) report on a therapeutic outcome(s), such as tumor response, improvement in survival, or measured
improvement in quality of life; and 3) describe
clinical findings in sufficient detail that a meaningful evaluation can be
made. Separate levels of evidence scores are assigned to qualifying human
studies on the basis of statistical strength of the study design and
scientific strength of the treatment outcomes (i.e., endpoints) measured. The
resulting two scores are then combined to produce an overall score. A table
showing the levels of evidence scores for qualifying human studies cited in
this summary is presented below. For an explanation of the scores and
additional information about levels of evidence analysis of CAM treatments for
cancer, please click on the following link: Levels of Evidence Analysis
for Human Studies of Cancer Complementary and Alternative Medicine.
Cartilage (Bovine and Shark) Summary:
Reference Numbers and the Corresponding Levels of Evidence
Strength of Study Design
Strength of Endpoints Measured
||3iii Nonconsecutive Case Series
||Diii Indirect Surrogates -- Tumor Response Rate
||3iii Nonconsecutive Case Series
||Diii Indirect Surrogates -- Tumor Response Rate
||3iii Nonconsecutive Case Series
||Diii Indirect Surrogates -- Tumor Response Rate
Glossary of Terms
Having to do with the abdomen, which is the part of the body between the chest
and the hips that contains the pancreas, stomach, intestines, liver,
gallbladder, and other organs.
acne: A disorder of the skin marked by
inflammation of oil glands and hair glands.
adenocarcinoma: Cancer that
begins in cells that line certain internal organs and that have glandular
amino acid sequence:
The arrangement of amino acids in a protein. Proteins can be made from 20
different kinds of amino acids, and the structure and function of each type of
protein are determined by the kinds of amino acids used to make it and how
they are arranged.
anal: Having to do with the anus, which
is the posterior opening of the large bowel.
angiogenesis: Blood vessel
formation. Tumor angiogenesis is the growth of blood vessels from surrounding
tissue to a sold tumor. This is caused by the release of chemicals by the
inhibitor: A substance that may prevent the formation of blood
vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth
of blood vessels from surrounding tissue to a solid tumor.
antiangiogenic: Refers to
reducing the growth of new blood vessels.
antibody: A type of protein
produced by certain white blood cells in response to a foreign substance
(antigen). Each antibody can bind to only a specific antigen. The purpose of
this binding is to help destroy the antigen. Antibodies can work in several
ways, depending on the nature of the antigen. Some antibodies disable
antigens directly. Others make the antigen more vulnerable to destruction by
white blood cells.
to reducing inflammation.
antimetastatic: Refers to
aqueous: Having to do with water.
arthritis: A disease marked by
inflammation and pain in the joints.
astrocytoma: A tumor that begins
in the brain or spinal cord in small, star-shaped cells called astrocytes.
B cells: White blood cells that
develop from bone marrow and produce antibodies. Also called B lymphocytes.
basal cell carcinoma: A
type of skin cancer that arises from the basal cells, small round cells found
in the lower part (or base) of the epidermis, the outer layer of the skin.
binding agent: A substance
that makes a loose mixture stick together. For example, binding agents can be
used to make solid pills from loose powders.
bioavailable: The ability of a
drug or other substance to be absorbed and used by the body. Orally
bioavailable means that a drug or other substance that is taken by mouth can
be absorbed and used by the body.
carcinoma: Cancer that begins in
skin or in tissues that line or cover internal organs.
cartilage: A type of connective
tissue that contains cells (chondrocytes) surrounded by a tough but flexible
matrix. The cartilage matrix is made of several types of the protein collagen
and several types of proteoglycans, which are combinations of protein and long
sugar molecules called glycosaminoglycans. Chondroitin sulfate is the major
glycosaminoglycan in cartilage.
case series: A group or series
of case reports involving patients who were given similar treatment. Reports
of case series usually contain detailed information about the individual
patients. This includes demographic information (for example, age, gender,
ethnic origin) and information on diagnosis, treatment, response to treatment,
and follow-up after treatment.
cervix: The lower, narrow end of the
uterus that forms a canal between the uterus and vagina.
chemotherapy: Treatment with
chondrocytes: Cartilage cells.
They make the structural components of cartilage.
chondroitin sulfate: The
major glycosaminoglycan (a type of sugar molecule) in cartilage.
membrane: The membrane in hen's eggs that helps chicken embryos get
enough oxygen and calcium for development. The calcium comes from the egg
circulatory system: The
system that contains the heart and the blood vessels and moves blood
throughout the body. This system helps tissues get enough oxygen and
nutrients, and it helps them get rid of waste products. The lymph system,
which connects with the blood system, is often considered part of the
cisplatin: An anticancer drug that
belongs to the family of drugs called platinum compounds.
clinical study: A research
study in which patients receive treatment in a clinic or other medical
facility. Clinical study reports can contain results for single patients
(case reports) or many patients (case series or clinical trials).
clinical trial: A research
study that evaluates the effectiveness of new interventions in people. Each
study is designed to evaluate new methods of screening, prevention, diagnosis,
or treatment of a disease.
collagen: A fibrous protein found
in cartilage and other connective tissue.
collagenase: A type of enzyme
that breaks down the protein collagen.
alternative medicine: CAM. Forms of treatment in addition to
(complementary) or instead of (alternative) standard treatments. These
practices include dietary supplements, megadose vitamins, herbal preparations,
special teas, massage therapy, magnet therapy, spiritual healing, and
complete response: The
disappearance of all signs of cancer. Also called a complete remission.
conjunctiva: A membrane that
lines the inner surface of the eyelid and also covers the front part of the
eye. Conjunctivitis is inflammation of the conjunctiva.
In a clinical trial, the group that does not receive the new treatment being
studied. This group is compared to the group that receives the new treatment,
to see if the new treatment works.
controlled study: An
experiment or clinical trial that includes a comparison (control) group.
A currently accepted and widely used treatment for a certain type of disease,
based on the results of past research. Also called conventional treatment.
cornea: The transparent part of the
eye that covers the iris and the pupil and allows light to enter the inside.
cultured cell line: Cells
of a single type that have been grown in the laboratory for several
generations (cell divisions).
dermatitis: Inflammation of the
diameter: The length of a straight
line that extends from one edge of a tumor or other object that is circular or
spherical in shape through its center and to the opposite edge. It is a
measure of size.
dysgeusia: A bad taste in the
mouth. Also called parageusia.
dyspepsia: Upset stomach.
edema: Swelling caused by excess fluid
in body tissues.
embryo: Refers to an early stage in
the development of a plant or an animal. In vertebrate animals, this stage
lasts from shortly after fertilization until all major body parts appear. In
particular, in humans, this stage lasts from about 2 weeks after fertilization
until the end of the seventh or eighth week of pregnancy.
endothelial cell: The main
type of cell found in the inside lining of blood vessels, lymph vessels, and
enema: The injection of a liquid
through the anus into the large bowel.
enzyme: A protein that speeds up the
rate at which chemical reactions take place in the body.
Patients whose response to a treatment can be measured because enough
information has been collected.
filler: An inactive substance used to
make a product bigger or easier to handle. For example, fillers are often
used to make pills or capsules because the amount of active drug is too small
to be handled conveniently.
gliosarcoma: A type of glioma.
glycosaminoglycan: A type
of long, unbranched polysaccharide molecule. Glycosaminoglycans are major
structural components of cartilage and are also found in the cornea of the
hemorrhoid: An enlarged or
swollen blood vessel, usually located near the anus or the rectum.
hepatitis: Inflammation of the
hormone therapy: Treatment
of cancer by removing, blocking, or adding hormones. Also called hormone
therapy or endocrine therapy.
hypercalcemia: Abnormally high
hyperglycemia: Abnormally high
hypotension: Abnormally low
hypothesis: A tentative proposal
made to explain certain observations or facts that requires further
investigation to be verified.
in vitro: In the laboratory
(outside the body). The opposite of in vivo (in the body).
in vivo: In the body. The opposite
of in vitro (outside the body).
inflammation: A response of
redness, swelling, pain, and a feeling of heat in certain areas, which is
meant to protect tissues affected by injury or disease.
intraperitoneal: IP. Within
the peritoneal cavity (the area that contains the abdominal organs).
intravenous: IV. Into a vein.
keratan sulfate: A
glycosaminoglycan (a type of polysaccharide) found in cartilage and in the
cornea of the eye.
lymphocyte: White blood cells.
Lymphocytes have a number of roles in the immune system, including the
production of antibodies and other substances that fight infection and
macrophage: A type of white blood
cell that surrounds and kills microorganisms, removes dead cells, and
stimulates the action of other immune system cells.
malignant: Cancerous; a growth
with a tendency to invade and destroy nearby tissue and spread to other parts
of the body.
metalloproteinase: A member of a group of enzymes that can break down
proteins, such as collagen, that are normally found in the spaces between
cells in tissues (i.e., extracellular matrix proteins). Because these enzymes
need zinc or calcium atoms to work properly, they are called
metalloproteinases. Matrix metalloproteinases are involved in wound healing,
angiogenesis, and tumor cell metastasis.
mesenteric membrane: The peritoneal membrane that attaches
the intestines to the abdominal wall near the back.
metastasis: The spread of cancer
from one part of the body to another. Tumors formed from cells that have
spread are called "secondary tumors," and contain cells that are like those in
the original (primary) tumor. The plural is metastases.
metastatic: Having to do with
metastasis, which is the spread of cancer from one part of the body to
milligram: A measure of weight. A
milligram is approximately 450,000-times smaller than a pound and 28,000-times
smaller than an ounce.
milliliter: A measure of volume
for a liquid. A milliliter is approximately 950-times smaller than a quart
and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic
centimeter (cc) of liquid are the same.
millimeter: A measure of length.
A millimeter is approximately 26-times smaller than an inch.
molecular mass: The sum of
the atomic masses of all atoms in a molecule, based on a scale in which the
atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16,
respectively. For example, the molecular mass of water, which has two atoms
of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16).
molecule: A chemical made up of
two or more atoms. The atoms in a molecule can be the same (an oxygen
molecule has two oxygen atoms) or different (a water molecule has two hydrogen
atoms and one oxygen atom). Biological molecules, such as proteins and DNA,
can be made up of many thousands of atoms.
myeloma: Cancer that arises in
plasma cells, a type of white blood cell.
nonmalignant: Not cancerous.
oral: By or having to do with the
osteoporosis: A condition that
is characterized by a decrease in bone mass and density, causing bones to
pancreas: A glandular organ located
in the abdomen. It makes pancreatic juices, which contain enzymes that aid in
digestion, and it produces several hormones, including insulin. The pancreas
is surrounded by the stomach, intestines, and other organs.
partial response: The
shrinking, but not complete disappearance, of a tumor in response to therapy.
Also called partial remission.
phase I trial: Phase I trials
are the first step in testing a new treatment in humans. These studies test
the best way to give a new treatment (for example, by mouth, intravenous
infusion, or injection), and the best dose. The drug is usually given in
progressively higher doses to determine the highest dose that does not cause
harmful side effects. Because little is known about the possible risks and
benefits of treatments being tested, phase I trials usually include only a
limited number of patients who have not been helped by other known treatments.
phase I/II trial: A trial
to study the safety, dosage levels, and response to a new treatment.
phase II trial: Phase II
trials focus on learning whether the new treatment has an anticancer effect
(for example, whether it shrinks a tumor, or improves blood test results), and
whether it is effective for a particular type of cancer.
phase III trial: Phase III
trials compare the results of people taking a new treatment with the results
of people taking the standard treatment (for example, which group has better
survival rates, and/or fewer side effects). In most cases, studies move into
phase III trials only after a treatment shows promise in phases I and II.
Phase III trials may include hundreds of people around the country or the
placebo: An inactive substance that
looks the same as, and is administered in the same way as, a drug in a
polysaccharide: A type of
carbohydrate. It contains sugar molecules that are linked together chemically.
Cancer that is increasing in scope or severity.
proteoglycan: A molecule that
contains both protein and glycosaminoglycans, which are a type of
polysaccharide. Proteoglycans are found in cartilage and other connective
psoriasis: A chronic disease of
the skin marked by red patches covered with white scales.
quality of life : The
overall enjoyment of life. Many clinical trials measure aspects of a person's
sense of well-being and ability to perform various tasks in order to assess
the effects that cancer and its treatment have on the person.
radiation therapy: The use
of high-energy radiation from x-rays, neutrons, and other sources to kill
cancer cells and shrink tumors. Radiation may come from a machine outside the
body (external-beam radiation therapy) or from materials (radioisotopes) that
produce radiation that are placed in or near a tumor or in the area where
cancer cells are found (internal radiation therapy, implant radiation, or
brachytherapy). Systemic radiation therapy involves giving a radioactive
substance, such as a radiolabeled monoclonal antibody, that circulates
throughout the body. Also called radiotherapy.
randomized: Describes an
experiment or clinical trial in which animal or human subjects are assigned by
chance to separate groups that compare different treatments.
trial: A study in which the participants are assigned by chance to
separate groups that compare different treatments. Neither the researcher nor
the participant can choose the group. Using chance to assign people means
that the groups will be similar and that the treatments they receive can be
compared objectively. At the time of the trial, it is not known which of the
treatments is best. It is the patient's choice to be in a randomized trial or
recurrent cancer: Cancer
that has returned, at the same site as the original (primary) tumor or in
another location, after the tumor had disappeared.
Inflammation of the intestines, but usually only of the small intestine. Also
called Crohn's disease.
regression: A decrease in the
extent or size of cancer.
renal cell cancer: Cancer
that develops in the lining of the renal tubules, which filter the blood and
response: In medicine, an
improvement related to treatment.
retrospective: Looking back at
events that have already taken place.
sarcoma: A cancer of the bone,
cartilage, fat, muscle, blood vessels or other connective or supportive
scleroderma: A chronic disorder
marked by hardening and thickening of the skin. Scleroderma can be localized
or it can affect the entire body (systemic).
scrotum: In males, the external sac
that contains the testicles.
selection bias: An error in
choosing the individuals or groups to take part in a study. Ideally, the
subjects in a study should be very similar to one another and to the larger
population (for example, all individuals with the same disease or condition)
from which they are drawn. If there are important differences, the results of
the study may not be valid.
skeleton: The framework that
supports the soft tissues of vertebrate animals and protects many of their
internal organs. The skeletons of vertebrates are made of bone and/or
carcinoma: Cancer that begins in squamous cells, which are thin, flat
cells resembling fish scales. Squamous cells are found in the tissue that
forms the surface of the skin, the lining of the hollow organs of the body,
and the passages of the respiratory and digestive tracts. Also called
stable disease: Cancer that
is not decreasing or increasing in extent or severity.
stage: The extent of a cancer within
the body, including whether the disease has spread from the original site to
other parts of the body. Staging refers to the determination of the extent of
non-small cell lung cancer: Cancer has spread to structures near the
lung; to the lymph nodes in the area that separates the two lungs
(mediastinum); or it has spread to the lymph nodes on the other side of the
chest or in the neck. Stage III is further divided into stage IIIA (usually
can be resected) and stage IIIB (usually cannot be resected).
subcutaneous: Beneath the skin.
T cell: One type of white blood cell
that attacks virus-infected cells, foreign cells, and cancer cells. They also
produce a number of substances that regulate the immune response.
therapeutic: Used to treat
disease and help healing take place.
topical: On the surface of the body.
Chronic inflammation of the colon that produces ulcers in its lining. This
condition is marked by abdominal pain, cramps, and loose discharges of pus,
blood, and mucus from the bowel.
endothelial growth factor: Also known as VEGF. A substance made by
cells that stimulates new blood vessel formation.
white blood cell: Refers to
cells in the immune system that help the body fight infection and disease.
White blood cells include lymphocytes, granulocytes, macrophages, and others.
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