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. 2010;102(12):859-865.
Multicenter, randomized, double-blinded, placebo-controlled phase III trial. Three hundred seventy-nine patients with unresectable stage III non-small cell lung cancer (NSCLC) were enrolled between June 5, 2000, and February 6, 2006. All patients received chemotherapy, including a platinum-based agent, and radiotherapy. Patients were randomly assigned in a 1:1 ratio to receive either 120 ml of AE-941 (Neovastat) (n=188) or an equal dose of placebo (n=191) orally twice daily. The groups were stratified for stage (IIIA or IIIB), chemotherapy regimen, and gender. Assessment of tumor status with computed tomography (CT) was made at baseline, before thoracic radiotherapy (which began day 50), and at 6 weeks post radiotherapy. The primary endpoint was overall survival. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), tumor response rate, and toxic effects.
There was no statistically significant difference in overall survival in those taking AE-941 versus placebo: 14.4 months (95% CI=12.6–17.9 months) vs. 15.6 months (95% CI=13.8–18.1 months). There was also no statistically significant difference between the AE-941 and placebo groups in any of the the secondary endpoints of the trial. Median TTP=11.3 months (95% CI =9.0–16.8 months) in AE-941 vs. 10.7 months (95% CI=9.5–21.6 months) in the placebo group. Similar results were obtained for progression-free survival.
The use of shark cartilage as an alternative cancer treatment has been touted in lay media for many years. In 1992 William Lane published Sharks Don’t Get Cancer: How Shark Cartilage Could Save Your Life, which coincided with a product he sold, shark cartilage extract (Benefin). The use of shark cartilage is an interesting story of the best and worst in the marketing and development of natural agents. While a product was being sold on the market, much of the scientific community dismissed its use out of hand based on hyperbole and lack of evidence. Meanwhile, there was diligent pursuit of evidence of its anticancer activity by the Canadian pharmaceutical company Aeterna Zentaris, owners of AE-941 (Neovastat).
Up until 2003, AE-941 appeared to be a legitimately promising agent, with data accumulating on its anticancer effects both in vitro and in vivo. This included a 2002 study of advanced cancers that showed a cohort of renal cell cancer patients (n=22) had improved survival in the high-dose (240 ml/d) group compared with the low-dose (60 ml/d) group (16.3 vs. 7.1 months).1 However, a phase III study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2003 reported there was no benefit to overall survival when used as a sole agent in patients with kidney cancer refractory to immunotherapy.2
The current study, which is much larger and better controlled than any previously published trials, now provides sufficient evidence to refute the use of shark cartilage in patients with NSCLC, and to dampen any enthusiasm of its use as an anticancer agent in general.
The current study . . . provides sufficient evidence to refute the use of shark cartilage.
AE-941 is a standardized, water-soluble shark cartilage extract. The precise composition of the extract is not disclosed, but there is presumption that proteins in the extract are responsible for its activity. In vitro, it has been shown to induce endothelial cell apoptosis, inhibit matrix metalloproteinases, and inhibit vascular endothelial growth factor.3,4,5 Given orally in a mouse, it has demonstrated antimetastatic activity.6
This favorable in vitro and in vivo data led to an open-label phase I–II dose escalation study assessing AE-941 (30, 60, 120, and 240 ml/d) in 80 patients with NSCLC. In this small trial there was a statistically significant improvement in survival in patients with Stage III/IV NSCLC (n=48) receiving the higher doses. Median survival time for the high-dose group was 6.1 months vs. 4.6 months in the low dose group (P=0.26).7
The current phase III trial of NSCLC is much larger and better controlled than the pilot study. Although recruitment was stopped before the target sample size of 756 patients was met, the final sample size of 384 patients was adequate for statistical analysis. At years 1, 3, and 5, the overall survival rate in the AE-941 group was 59%, 25%, and 14% respectively. In the placebo group, the overall survival rates at 1, 3, and 5 years were 61%, 21%, and 14% respectively. No secondary endpoints resulted in statistical benefit either. This multicenter trial included both academic and community clinics and was well controlled and designed.
It is essential as practitioners that we stay apprised of new information on natural agents that are reputed to have anticancer effects. We should neither be swayed by the popular press nor be dismissive of ideas before all of the evidence is assessed. Shark cartilage is one example of a promising product in vitro that has just not proven itself in large clinical studies. While still sold on the market, there is insufficient evidence to warrant its use, and evidence provides direct refutation of its use in NSCLC. Of course, the supplement also takes an ecologic toll on the shark population, a separate but valid concern regarding its widespread use. The National Cancer Institute provides a comprehensive listing of all of the clinical trial data on the various shark cartilage products.
AE-941 is a complex natural product, not a single agent. The company claims it is standardized, although there is no methodology or component breakdown to ensure replication or even consistency from batch to batch. The current study did not disclose batch numbers, so this is an unanswered question regarding the current study. The dose may not have been adequate, although the dose used in the study, 240 ml/d, was the highest level yet tested in a phase I study. The tolerable upper dose has not been set. Lastly, when given orally components in AE-941 may be broken down by digestion before reaching the bloodstream. Without any blood parameters of either ingredients or other blood markers to track, it is unclear whether AE-941 was adequately absorbed intact.
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