Human/Clinical Studies
At least a dozen clinical studies (MDA-ID-99303, NCCTG-971151, and AETERNA-AE-MM-00-02) of cartilage as a treatment for cancer
have been, or are being, conducted since the early 1970s;[1-9] Reviewed in [10-16] (see the table at the end of this section) however, results
from only six studies have been published in peer-reviewed scientific
journals.[1,2,4,8,9,17] It is not clear whether any of the patients in the conducted
studies were children.
In the only randomized trial published in a peer-reviewed scientific journal, 83 incurable breast cancer and colorectal cancer patients were randomly assigned to receive either shark cartilage or placebo, in addition to standard care. No difference was observed in survival or quality of life between those receiving shark cartilage and those receiving placebo.[8] Additional clinical studies are under way; however, 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)
powdered preparation of bovine (cow) cartilage, as a treatment for various solid
tumors.[1,2] One of these studies was a case series that included 31
patients;[1] the other was a phase II clinical trial that
included nine patients.[2]
In the case series,[1] 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, radiation
therapy, hormonal 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, ten 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 recurrent cancer.
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 most patients.
In the phase II trial,[2] 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 administered 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. One patient (with metastatic renal cell carcinoma) reportedly 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, and ratio of helper T cells to cytotoxic T cells) was
observed, though increased numbers of T cells were found in three
patients.
Partial results of a third clinical study of Catrix are described in an
abstract submitted for presentation at a scientific conference,[3] but
complete results of this study have not been published in a peer-reviewed
scientific journal. In the study, 35 patients with metastatic 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.[4] 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 ten 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,[5,6] 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.[5] These three
studies enrolled 20 patients with breast cancer,[5] 12 patients with prostate
cancer,[5] and 12 patients with primary brain tumors.[6] All patients had
been treated previously with conventional therapy. No other anticancer
treatment was allowed concurrently with cartilage therapy. In two of the
studies,[5] the name of the cartilage product was not identified; however, in
the third study,[6] the commercially available product BeneFin was used. Ten
patients in each study completed at least 8 weeks of treatment and therefore were considered evaluable for response. No complete responses or
partial responses were observed in any of the studies. Two evaluable patients
in the breast cancer study were reported to have stable disease that lasted 8
weeks or more; two evaluable patients in the brain tumor study had stable
disease that lasted 20 weeks or more; and three evaluable patients in the
prostate cancer study had stable disease that also lasted 20 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.[9,18] Reviewed in [11,10,16] It has been reported that AE-941/Neovastat has little toxicity. Reviewed in [10,11,16] In addition, there is evidence from a randomized clinical trial that examined the effect of AE-941/Neovastat on angiogenesis associated with surgical wound repair that this product contains at least one antiangiogenic component that is orally bioavailable.[18]
AE-941/Neovastat was administered to 331 patients with advanced solid tumors (including lung, prostate, breast, and kidney tumors) in two phase I/II trials. Reviewed in [10] The results of these trials, however, have not been fully reported. A retrospective analysis involving a subgroup of patients with advanced non-small cell lung cancer suggests that AE-941/Neovastat is able to lengthen the survival of patients with this disease. Reviewed in [10] Furthermore, in a prospective analysis involving 22 patients with refractory renal cell carcinoma, survival was longer in patients treated with 240 mL /day AE-941/Neovastat than in patients treated with only 60 mL/day.[7,17] Reviewed in [10]
In 2003, the results of a phase I/II trial of AE-941/Neovastat in 80 patients with advanced non-small cell lung cancer (NSCLC) reported that there was a significant survival advantage for patients receiving the highest doses (2.6 mL/kg/day) of AE-941/Neovastat. A survival analysis of 48 patients with unresectable stage IIIA, IIIB, or IV NSCLC showed a median survival advantage of P = .0026 in patients receiving the highest doses. The trial was principally conducted to explore the safety and efficacy of orally administered AE-941/Neovastat when administered in escalating doses (30, 60, 120, and 240 mL/day). No dose-limiting toxicity was found. No tumor response was observed.[9]
In 2001, a phase II trial (AETERNA-AE-MM-00-02) of AE-941/Neovastat was initiated in patients with relapsed or refractory multiple myeloma. This trial closed approximately 1 year later, and no results have been reported.[19]
Two randomized phase III trials of AE-941/Neovastat in patients
with advanced cancer have been approved by the U.S. Food and Drug Administration (FDA). In one trial (MDA-ID-99303), which is completed, treatment
with oral AE-941/Neovastat plus chemotherapy and radiation therapy
was compared with treatment with placebo plus the same chemotherapy and radiation
therapy in patients with
stage III NSCLC. In the second trial, which closed to patient recruitment in 2002, treatment
with oral AE-941/Neovastat was compared with treatment with placebo in
patients with metastatic renal cell carcinoma. Results from this second phase III trial have not been reported in the peer-reviewed scientific literature.[20] Despite being granted orphan drug status by the FDA in 2002 for use of AE-941/Neovastat in the treatment of renal cell carcinoma, the company that produces AE-941/Neovastat, Aeterna Laboratories, announced in early 2004 that this application would be discontinued in favor of a focus on the treatment of NSCLC.[20,21]
Cartilage Use in Cancer Treatment: Clinical Studies With Therapeutic Endpointsa,b
Reference Citation(s)
|
Type of Study
|
Type(s) of Cancer
|
Cartilage
Product (Source)
|
No. of Patients: Treated; Control
|
Strongest Benefit Reportedc
|
Concurrent Therapyd
|
Level
of Evidence Scoree
|
[1] |
Nonconsecutive case series
|
Various advanced or recurrent |
Catrix (bovine) |
31;
None |
Complete response, 19 patients |
Yes |
3iiiDiii |
[2] |
Phase II trial |
Various metastatic |
Catrix (bovine) |
9;
None |
Complete response, 1
patient, metastatic renal cell carcinoma |
No |
3iiiDiii |
[3] |
Phase II trial |
Metastatic renal cell |
Catrix (bovine) |
35;
None |
Partial response, 3 of
22 evaluable patients |
Unknown |
Nonef |
[10,17] |
Two phase I/II trialsg |
Various advanced, refractory solid tumors |
AE-941/ Neovastat (shark) |
331;
None |
Improved survival, higher versus lower
doses, patients with stage III/IV non-small cell lung cancer (unplanned retrospective analysis), and patients with refractory renal cell carcinoma (prospective analysis) |
Unknown |
Nonef |
[9] |
Phase I/II trial |
Advanced non-small cell lung cancer
|
AT-941/Neovastat (shark)
|
80; None
|
No dose-limiting toxicity found. Improved survival time in patients receiving the highest doses when survival analysis was conducted, and stable disease for greater number of patients receiving higher doses. No tumor response observed. |
Yes or refused standard therapy |
None |
[4] |
Phase I/II trial |
Various advanced solid tumors |
Cartilade (shark) |
60;
None |
Stable disease for 12 weeks or more, 10 of
50 evaluable patients |
No |
3iiiDiii |
[5] |
Phase II trial |
Metastatic, refractory breast |
Unknown (shark) |
20;
None |
Stable disease for 8 weeks or more, 2 of
10 evaluable patients |
No |
Nonef |
[5] |
Phase II trial |
Metastatic, hormone- refractory prostate |
Unknown (shark) |
12;
None |
Stable disease for 20 weeks or more, 3 of
10 evaluable patients |
No |
Nonef |
[6] |
Phase II trial |
Various advanced brain |
BeneFin (shark) |
12;
None |
Stable disease for 20 weeks or more, 2 of
10 evaluable patients |
No |
Nonef |
[8] |
Phase III randomized, placebo-controlled, double-blind trial (2 arms) |
Breast and colorectal |
BeneFin (shark) |
42; 41 |
No statistically significant difference |
No |
1i |
No. = number.
|
aSee text and glossary for additional information and definitions of most
terms.
|
bOther clinical studies have been conducted, but no results have been
reported.
|
cStrongest evidence reported that the treatment under study has
anticancer activity or otherwise improves the well-being of cancer patients.
|
dChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy
given/allowed at the same time as cartilage therapy.
|
eFor information about Levels of Evidence analysis and an explanation of
the level of evidence scores, see Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
|
fStudy results reported in review article or abstract form only; insufficient information presented for Level of Evidence analysis.
|
gInsufficient information available to describe these studies separately.
|
References
-
Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
[PUBMED Abstract]
-
Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985.
[PUBMED Abstract]
-
Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
-
Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998.
[PUBMED Abstract]
-
Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
-
Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
-
Batist G, Champagne P, Hariton C, et al.: Dose-survival relationship in a phase II study of Neovastat in refractory renal cell carcinoma patients. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1907, 2002.
-
Loprinzi CL, Levitt R, Barton DL, et al.: Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 104 (1): 176-82, 2005.
[PUBMED Abstract]
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Latreille J, Batist G, Laberge F, et al.: Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer. Clin Lung Cancer 4 (4): 231-6, 2003.
[PUBMED Abstract]
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Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001.
[PUBMED Abstract]
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AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
[PUBMED Abstract]
-
Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. New York, NY: WW Norton & Company, 1998, pp 197-200.
-
Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. Last accessed October 30, 2008.
-
Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995.
-
Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
[PUBMED Abstract]
-
AE 941. Drugs R D 5 (2): 83-9, 2004.
[PUBMED Abstract]
-
Batist G, Patenaude F, Champagne P, et al.: Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels. Ann Oncol 13 (8): 1259-63, 2002.
[PUBMED Abstract]
-
Berbari P, Thibodeau A, Germain L, et al.: Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. J Surg Res 87 (1): 108-13, 1999.
[PUBMED Abstract]
-
Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.
[PUBMED Abstract]
-
Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.
[PUBMED Abstract]
-
New treatment option for postmenopausal women with early breast cancer. Expert Rev Anticancer Ther 2 (6): 617, 2002.
[PUBMED Abstract]
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