Human/Clinical Studies

Powdered Cartilage Products
Aqueous Extracts of Cartilage

Since the early 1970s, at least a dozen clinical trials (MDA-ID-99303 ¹, NCCTG-971151 ², and AETERNA-AE-MM-00-02 ³) of cartilage as a treatment for people with cancer have been (or are being) conducted;[1-9] Reviewed in [10-16] (refer to the table ⁴ at the end of this section) however, results from only seven 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 these studies were children.

In the first 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 treatment for people with cancer.

Two of the three published clinical studies evaluated the use of Catrix, the previously mentioned (refer to the Laboratory/Animal/Preclinical Studies ⁵ section of this summary for more information) 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 9 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 also treated with topical preparations. 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 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 1 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.

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. Following Catrix therapy, 2 of the 22 evaluable patients were reported to have stable disease, and 17 were reported to have progressive disease. No relationship between Catrix dose and tumor response could be established in this study.

The third published study of cartilage as a treatment for people with 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.

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.

The safety and the efficacy of AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has 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 (NSCLC) 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 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, and 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 AE-941/Neovastat being granted orphan drug status by the FDA in 2002 for use 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]

In 2010, the results of a randomized, double-blind, placebo-controlled phase III trial aimed at assessing the effect of adding AE-941 to chemotherapy and radiation therapy on the overall survival of patients with nonresectable stage III NSCLC were reported. A total of 379 eligible patients received induction chemotherapy followed by concurrent chemotherapy with chest radiation therapy; participating centers used one of two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. No statistically significant difference in overall survival was observed between the group (n = 188) receiving chemotherapy and radiation therapy plus AE-941 (120 mL administered orally twice daily) and the group receiving chemotherapy and radiation therapy plus placebo (n = 191). Both AE-941 and placebo were well tolerated.[22]

References

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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. 
   
   
4. 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]
   
   
5. 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. 
   
   
6. 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. 
   
   
7. 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. 
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.  [PUBMED Abstract]
    
    
12. 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. 
    
    
13. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. ⁹ Last accessed January 11, 2012. 
    
    
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17. 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]
    
    
18. 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]
    
    
19. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.  [PUBMED Abstract]
    
    
20. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.  [PUBMED Abstract]
    
    
21. New treatment option for postmenopausal women with early breast cancer. Expert Rev Anticancer Ther 2 (6): 617, 2002.  [PUBMED Abstract]
    
    
22. Lu C, Lee JJ, Komaki R, et al.: Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst 102 (12): 859-65, 2010.  [PUBMED Abstract]