Shark Cartilage

Shark cartilage

Unproved, unconventional. And alternative methods of cancer treatment are particularly appealing to patients with advanced-stage cancer. Despite the modest gains achieved in the treatment of adult malignancies with multimodality therapy in the last decade, the majority of patients with advanced-stage cancer die of refractory and disseminated disease. In an effort to control their destiny and improve their quality and length of life, many patients turn to alternative medicine. These alternatives are used alone or in combination with conventional anticancer therapy. Alternative medicine includes;

1. metabolic, pharmaceutical, herbal, or immune therapies
2. dietary alterations or supplementation with high-dose multivitamins, minerals, antioxidants, or other nonnutrient agents
3. alternative therapists or healing methods (eg, acupuncture, hypnosis, spiritual therapy, mind-body therapy)

The use of alternative cancer therapy ranges from 9% to 50%, but these may be underestimated because patients are reluctant to report their use of unconventional therapies. In recognition of the popular use of alternative therapy in cancer patients, the National Cancer Institute created the Office of Alternative Medicine in 1992 to support clinical research in the field.

Many of the more publicized unconventional anticancer therapies engendered controversy, litigaion, and exuberant media coverage. In the laetrile saga, for example, the ensuring controversy and the widespread but unproved use of the agent led to double-blind, controlled, randomized trials that showed its lack of anticancer activity.

Shark and other animal cartilage products have been used with success since the 1950s to promote wound healing and the treat chronic inflammatory and other nonneoplastic disorder. It is known that isolates from shark cartilage (SC) are antiangiogenic.

The growth and metastasis of malignant tumors are dependent on angiogenesis. Angiogenesis and antiangiogenesis are multifactorial and counteracting mechanisms that involve a number of stimulatory and inhibitory factors secreted by tumor cells, nonneoplastic cellswithin the tumor, and by macrophages, mast cells, and endothelial cells. These include fibroblast growth factor-alpha and -beta, platelet-derived endothelial-cell growth factor, vascular permeability factor, transforming growth factor-alpha and -beta, angiogenin, thrombospondin, and tumor necrosis factor, A number of inhibitors of tumor angiogenesis have been isolated.

Expect for these in vitro studies, little has been published in peer-reviewed scientific journals or presented at scientific meetings regarding the antitumor activity of crude SC or SC isolates in animal xenograft models. No data are available on absorption, pharmacokinetics, bioavilability, stability, immunomodulation, dose escalation, synergy (or antagonism) with other anticancer agents, or toxicity in cancer patients treated with SC preparations. This is because the nature of the antiangiogenic moiety in DC is unknown. An anecdotal report, later aired on network television, summarized the experience of 19 patients treated in Cuba, of whom 12 had tumor regression after 6 weeks of therapy. One other published study was flawed in study design and the quantification of the major end points, response and quality of life.

SC has not received US Food and Drug Administration approval as an anticancer agent. A number of products, marketed and sold for bone and joint health, are readily available as over-the-counter products in supermarkets and health food stores throughout the United States or through mail-order nutritional supplement companies. Jacobs2 estimated that 50,000 Americans used SC as an adjunct to or as the sole therapy for their cancer. Because of the popular but uncontrolled use of SC and the absence of any published phase I/II clinical trials, we launched this phase I/II openlabel, nonrandomized study of SC as a single agent to evaluate its safety and efficancy in adults with advanced-stage cancer and to determine its effect on quality of life.

Eligibility Criteria

Adults patients (aged >=15 years) with histologically confirmed, advanced-stage (stage III to IV), previously treated, refractory, recurrent, and/or metastatic cancer were entered onto the study from January 1995 through September 1996. Areview of submitted sliders, surgical pathology reports, or surgical specimens or needle biopsies of fresh tissue confirmed the diagnosis of cancer. Only patients with stages III to IV cancers of the lung, breast, colorectum, prostate, bladder, and brain and non-Hodgkin's lymphoma were eligible. The interval between prior anticancer therapy and entry onto the study was 3 weeks. Patients with primary brain tumors required an interval of 45 days from prior cranial radiation therapy before enrollment. The protocol was amended in September 1995 to permit the entry of patients who refused conventional anticancer therapy after being fully informed of the available conventional therapies and their greater likelihood of efficacy.

All patients had objective measurable disease determined by physical examination and appropriate medical imaging studies. Patients with only increased levels of a surrogate biologic marker of persistent or recurrent disease (eg. Elevated prostate-specific antigen levels without measurable disease) were ineligible. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a projected life expectancy of at least 12 weeks. SC was the only taken or were taking SC at 20% or greater of the protocol prescribed dose (1 g/kg daily) for 1 month or more were excluded. Pregnant and lactating women were also excluded. The protocol was approved by the and the Institutional Review Boards of the two participating sites (Midwestern Regional Medical Center, Zion, IL, and Cancer Treatment Centers of America at Maryview Hospital, Prtsmouth, VA). Informed consent was obtained from all patients enrolled onto the study. The SC used in the study (Cartilade) was generously provided to study patients by Cartilage USA, Elmsford, NY.

Study Design

Baseline evaluation included a complete history and physical examination. The specific details of all prior anticancer therapy were obtained, which included modality of treatment, first and last date of treatment, surgical procedures, dose schedule of all chmotherapeutic agents, total dose, and response. Baseline laboratory and imagin studies included complete blood count and differential count, chemistry profile (SMA-21), prothrombin time, partial thromoboplastin time, and immune function panel (T and B cell subsets, natural-killer cell function, and serum immunoglobulin, tumor nectosis factor, and interleukin-2 levels). Tumor markers and medical imaging studies appropriate for the specific tumor site were obtained to document the extent of disease. Cross-dimensional diameters of all measurable lesions were determine whenever possible. Assessable but nonmeasurable lesions (eg, positive bone scans) were monitored.

Quality of life was quantified with the previously validated Functional Assessment of Cancer Therapy-General (FACT-G) scale. This self-administered questionnaire evaluates social, physical, social/family, emotional, and functional well-being and professional relationships and is sensitive to clinical change.

Patients were treated with SC powder, 1g/kg daily orally in three devided doses taken before meals. The powder (5 g/tsp) was mixed in fruit juice. Vanilla flavor (2% w/w of SC pwder) was added by the manufacturer approximately 6 months after the study was opened, but no adjustment in dosage was made.

Shark cartilage in advanced cancer

Patients were treated as outpatients and returned after 6 and 12 weeks for interval history, physical examination, laboratory and imaging studies, FACT-G score, evaluation of response, and documentation of adverse events. Patients received a 6-week supply of SC after the initial baseline evaluation. Compliance was determined by direct questioning of patients and confirmation of pharmacy records. The dose of SC was increased of 1.3 g/kg daily (30%) if there was no measurable response after 6 weeks of therapy. All patients received comprehensive meicaloncology care commensurate with their needs. This included active psychosocial support and a standard nutritional supplementation program that consisted of multivitamins, minerals, and antioxidants. Trained registered dietitians provided the specific details of a low-fat, high-vegetable, and high-fruit diet.

Standard criteria were used to evaluate objective clinical activity, subjective responses (quality of life), and toxicity (National Cancer Institute criteria). A complete response (CR) was defined as the complete disappearance of all tumor messes without the appearance of any new lesions and normalization of all clinical and laboratory signs and symptoms of active disease. A partial response (PR) was defined as a 50% or greater reduction of the products of the longest perpendicular diameters of the measured sentinel lesions without demonstrable new lesions elsewhere. Stable disease (SD) occurred when no new lesions appeared and no measurable lesions increased more than 25% in a cross-directional area. Progressive disease (PD) was defined as the appearance of new lesions and /or increase in the cross-sectional area of any previously known lesion by greater than 25%.

An adequate trial was 12 weeks of therapy. Off-study criteria were (1) pd, (2) the patient's desire to withdraw, (3) noncompliance, (4) unusual or unacceptable toxicity, or (5) emerging evidence that SC was of no benefit to patients with a similar tumor type.

The end points of the evaluation included response rate, time to tumor progression (date on study to documented PD), and quantitative changes in FACT-G scores.

Statistical Analysis

The trail was designed to enroll 12 assessable patients for each of seven tumor types, with an initial entry of 84 patients. Further accrual would be halted if no CR or PR were observed in each specific tumor type and the therapy would be judged inactive. If one or more CRs or PRs occurred among the 12 patients, another 25 patients were to be entered. Tumor types with four or more CRs or PRs were to be targeted for further study. The planned accrual was designed to provide a 90% likelihood of rejecting treatment with a true response rate of 5% or less of 20% or more. Data compiled at baseline, 6 weeks, and 12 weeks were analyzed by two-way analysis of variance by ranks. Preenty data of patients who became lost to follow-up (LTFU), withdrew, or refused further treatment were analyzed to determine if any features distinguished them from the other patients. Median values of quantities, such as age and days since diagnosis, were compared using Wilcoxon's rank-sum test, and categoric values (of quantities such as primary tumor site and off-study reason) were compared using ×2 tests and, for 2 × 2 tables, Fisher's exact tests.

Results

Response

The characteristics to the 60 study patients are listed in Table 1. There were 24 men (40%) and 36 women (60%). The median age of all patients was 63 years. Ninety-seven percent of the patients had stage IV disease. The two patients with unknown primary tumors at the time of study entry had probable stage IV breast cancer. The mean ECOG performance score was 1.02. One patient with non-small-cell lung cancer had not prior anticancer therapy.

Table 1. Patient Characteristics

	Tumor
	Brain	Breast	Colon	Lung	Lymph	Prostate	Total
Total no. entered	1	18	16	14	3	8	60
Assessable	1	13	10	14	2	8	47
Men	1	-	6	8	1	8	24
Women	-	18	10	6	2	-	36
Stage3	1	-	-	1	-	-	2
Stage4	-	18	16	13	3	8	58

Ten patients were not assessable for response or toxicity because they were LTFU or refused further therapy (RFT) before 6 weeks of treatment. Their median age (54 years) was significantly younger than the median age (63 years) of the overall study population.

Three patients with SD at 6 weeks were LTFU between 6 and 12 weeks. Patients who were LTFU, withdrew, or RFT were mostly women (10 v three). Expect for age, there were no distinguishing features between these groups and the entire study population.

The response and disposition of patients by tumor type are listed in Table 2. Five patients withdrew because of gastrointestinal toxicity. Five patients died of PD while undergoing therapy. Twenty-two patients (36.7%) had PD before or at the 6-week evaluation point (range, 4 days to 6 weeks). Five patients developed PD between 6 and 12 weeks of therapy. No CRs or PRs were observed, but 10 to 50 assessable patients (20%) had SD for 12 weeks or more (range, 12 to 45.7 weeks). The time to tumor progression of all study patients is shown in Fig 1.

Table 2. Response by Tumor Type

Response/ Off Study	Brain	Breast	Colon	Lung	Lymphoma	Prostate	Total
PD>=12Weeks(SD)	-	2	3	3	-	2	10
PD<12Weeks	-	2+	-	2	-	1	5
PD<=12Weeks(SD)	1	6	5	5	-	5	22
SD at 6 weeks	-	-	1	-	2	-	3
LFTU or RFT	-	5	5	-	-	-	10
Toxicity	-	2	1	1	1	-	5
Death	-	1+	1	3	-	-	5
Total	1	18	16	14	3	8	60

The characteristics of the 10 patients with SD for 12 weeks or more are listed in Table.3. All had stage IV disease (colorectal, three patients; lung, three patients; breast, two patients; prostate, two patients). The median time to tumor progression was 27 weeks, the mean +-SD was 28.8 +- 9.9 weeks, and the range was 18.6 to 45.7 weeks. Respective times for three patients were unavailable. The prostate-specific antigen levels in the two prostate cancer patients did not decrease during SD. One patients refused conventional therapy for non-small-cell lung cancer, started SC therapy 25.6 weeks after diagnosis, and had PD after 25 weeks of treatment, during which time his FACT-G scores declined from 84 to 67. One patient refused further therapy after 12 weeks.

A comparison of laboratory values in patients with SD and the entire study population showed slightly higher median tumor necrosis factor-alpha values at baseline (2.71 v 2.21 pg/mL) and at 6 weeks (2.67 v 2.27 pg/mL). The numbers of patients were too small to make meaningful statistical comparisons.

Quality of Life

The FACT-G scores of the 25 assessable patients with complete data are shown in Fig 2. There was no significant difference between those patients with FACT-G scores and those without regarding preentry characteristics or response to treatment. Among those with complete data, the median change from the baseline score to the 6-week score was -1.3 and -4.2 to the 12-week score was -2.4 points. In general, no overall improvement in quality of life was observed. In the group of patients with SD, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. There was no relationship between time to tumor progression and FACT-G scores, but there was evidence of a trend between time since diagnosis and improvement in quality of life scores. Within this group, patients who entered the study within 65 weeks of diagnosis had median FACT-G scores at baseline (n=17), 6 weeks (n=8), and 12 weeks (n=4) of 79.3, 79.8, and 64.5, respectively. The corresponding median scores in the entire study population for which data were available were 84, 79, and 76, respectively. The small number precluded meaningful statistical analysis.

Toxicity/Adverse Events

SD therapy with the dose schedule used in this study was generally well tolerated and was not associated with hematologic or biochemical toxicity. Of note, hypercalcemia was not observed. No patient developed hepatitis or abnormal liver function test.30

No effects were noted on measured immune function parameters (data not shown). Adverse events are recorded in Table 4. Toxicity was generally mild (grade 1) to moderate. Five episodes of grade 3 toxicity were recorded. Fourteen of the 20 reported adverse events were gastrointestinal (nausea, nine patients; vomiting three patients; constipation, two patients).

Discussion

The popularity and prevalence of SC as a potentially beneficial anticancer therapy is consumer driven. Until recently, it has bypassed conventional preclinical in vivo testing and conventional phase I/II clinical trials. There are no published data that unequivocally show the anticancer activity of SC in humans.

Earlier in vitro preclinical studies suggested that purified isolates from SC possessed antiangiogenic activity, but there are few studies that show activity against celllines from human or animal cancers or fresh tumor cells in vitro. Recent presentations by Canadian investigators suggested that a liquid extract from shark cartilage (Neovastat, Aeterna Laboratories, Quebec, Canada) inhibited blood vessel formation and endothelial cell proliferation in vitro. The agent had in vitro antitumor activity against MCF-7 human breast cancer, A2780 human ovarian adenocarcinoma, KB, human epidermoid carcinoma, and DA3 murine mammary adenocarcinoma cell lines. Neovastat inhibited tumor-cell growth in a murine mammary carcinoma xenograft model and was additive with cisplatin in the reduction of metastases in the Lewis lung carcinoma model in mice. The agent is undergoing phase I/II clinical trials in Canada and the United States. Preliminary results suggest some clinical benefit as measured by analgesic consumption, ECOG performance status, and weight.

Investigations in the field of antitumor angiogenesis have burgeoned recently as purified antiangiogenic factors have been identified and isolated, tested in classical prelinical studies, and subjected to early clinical trials. Promising agents include the following: TNP-470 (AGM-1470), a synthetic analogue of fumagillin; carboxyaminotriazole, a signal transduction inhibitor that blocks calcium influx; matrix metalloproteinase inhibitors; Tecogalan (Daiichi Pharmaceuticals, Tokyo, Japan), a polysaccharide; and interleukin-12. Unlike crude preparations or partially purified isolates that have been used in large doses up to 1 g/kg daily, purified antiangiogenic factors are active in micro gram per kilogram doses, and appear to be more practical and logical candidates for antiangiogenic therapy.

Naturally occurring and highly bioavailable isoflavone components of soya foods (genistein, daidzein) are antiangiogenic and have direct tumoricidal effects on cancer cells in vitro.Messina et al have reviewed the in vitro and in vivo evidence that supports the salutary role of soya components for the treatment and chemoprevention of cancer.

Reliable and objective comparative data on the antiangiogenic and anticancer activity of the SC preparations currently available as over-the-counter nutritional supplements are not available. One of the manufacturers and distributors of commercially available SC (Bio therapies, Inc/Cartilage Technologies, Inc, Elmhurst, NY) has cautioned against the lack of any proven anticancer activity of their marketed product. Others have launched vigorous public relations and advertising campaigns and, though cyberspace, have claimed the superiority of their product. They attributed the negative results reported here to the alleged inactivity of the investigational agent. Anecdotal and unconfirmed results from another web page reported "an overall response rate of about 25% "(eight of 35 patients), "improved quality of life in 100%", and a "decrease in bone pain in 50% of patients." These data have not been subjected to peer review.

One uncontrolled study of SC has been published.25 Fifteen of 21 patients were treated concomitantly with surgery, chemotherapy, or radiation therapy, with or without other unconventional therapies. SC 1 g/kg daily was used as adjuvant therapy in many of the patients who had no residual or measurable disease after they received primary therapy. It is impossible to determine whether the "61% reduction in tumor size" was attributable to SC therapy. Standard criteria were not used to evaluate response. Quality of life was reported as improved in 87% of the treated patients but the instrument, if any, used to quantify the measurement was not described. Thus, it is difficult to evaluate the contributory role of SC in these patients without an adequate control group. With this flawed study design, the results are inconclusive.

None of the 60 patients entered onto our study achieved a CR or PR, the standard benchmark of antitumor activity of a new, potentially beneficial, anticancer agent. More recently, such end points as time to tumor progression, duration of SC, and quality of life have been accepted in a new paradigm to evaluate the salutary effects of investigational anticancer agents in patients with advanced-stage disease.

The 10 patients in our study who had SD for 12 weeks or greater deserve special consideration. Reported studies of time to tumor progression in patients with advanced-stage cancer treated with supportive care alone or placebo versus experimental phase I/II chemotherapy are similar to the results observed with SC alone. It is recognized that scientific and statistical comparisons of this study with previously published data from double-blind, placebo-controlled trials may not be valid. However, the time to tumor progression in the respective placebo groups of patients treated with laetrile and hydrazine sulfate was similar to the time to tumor progression nated in the SC-treated patients who achieved SD. Unanswered is whether SC in combination with conventional chemotherapy or as adjuvant therapy in early-stage disease is beneficial.

Based on the results of this study, SC therapy with this dose schedule and route of administration in breast, colon, and lung cancer shouwed no anticancer activity. The significance of the SD rate of 16.7% of intent-to-treat patients and 20% of assessable patients is uncertain. The demonstration of efficacy will require randomized controlled trails with SC versus best supportive care or conventional salvage chemotherapy with or without SC. These issues my be moot with the recent identification of purified antiangiogenic factors (eg, angiostatin, endostatin) and the anticipated or imminent initiation of phase I/II trials.