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reference
Lu C, Lee JJ, Komaki R, et al. Chemoradiotherapy with or without AE-941 for stage III non-small cell lung cancer: a randomized phase III trial.J Natl Cancer Inst.2010;102(12):859-865.
design
Multicenter, randomized, double-blind, placebo-controlled phase III study. Between June 5, 2000 and February 6, 2006, 379 patients with unresectable stage III non-small cell lung cancer (NSCLC) were enrolled. All patients received chemotherapy, including a platinum-based agent, and radiation therapy. Patients were randomized 1:1 to receive either 120 mL of AE-941 (Neovastat) (n=188) or an equal dose of placebo (n=191) orally twice daily. Groups were stratified by stage (IIIA or IIIB), chemotherapy regimen, and gender. Assessment of tumor status using computed tomography (CT) was performed at baseline, before thoracic radiotherapy (which began on day 50), and 6 weeks after radiotherapy. The primary endpoint was overall survival. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), tumor response rate and toxic effects.
Key findings
There was no statistically significant difference in overall survival in patients taking AE-941 compared to 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 study's secondary endpoints. 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.
Effects on practice
The use of shark cartilage as an alternative cancer treatment has been touted in lay media for many years. In 1992 William Lane publishedSharks Don't Get Cancer: How Shark Cartilage Could Save Your Lifewhich coincided with a product he sold, shark cartilage extract (Benefin). The use of shark cartilage is an interesting story about the best and worst aspects of marketing and developing natural active ingredients. While a product was sold on the market, much of the scientific community flatly rejected its use due to exaggerations and lack of evidence. Meanwhile, Canadian pharmaceutical company Aeterna Zentaris, owner of AE-941 (Neovastat), carefully searched for evidence of its anti-cancer effects.
By 2003, AE-941 appeared to be a promising drug and data on its anti-cancer effects were accumulatingin vitroAndin vivo. These included a 2002 study in advanced cancers that showed that a cohort of patients with renal cell cancer (n=22) had improved survival (16.3 vs. 7.1 months) in the high-dose (240 mL/day) group compared to the low-dose (60 mL/day) group.1However, a phase III trial presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2003 found that there was no overall survival benefit when it was used as a sole agent in patients with kidney cancer that did not respond to immunotherapy.2
The current study, which is much larger and better controlled than any previously published study, now provides enough evidence to refute the use of shark cartilage in patients with NSCLC and to dampen any enthusiasm for its use as an anticancer drug 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 exact composition of the extract is not disclosed, but it is suspected 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.3,4,5Administered orally to a mouse, it showed anti-metastatic activity.6
That's cheapin vitroAndin vivoThe data led to a Phase I-II, open-label, dose-escalation study evaluating AE-941 (30, 60, 120, and 240 mL/day) in 80 patients with NSCLC. In this small study, there was a statistically significant improvement in survival in patients with stage III/IV NSCLC (n=48) who received the higher doses. The median survival time for the high-dose group was 6.1 months versus 4.6 months in the low-dose group (P=0.26).7
The current Phase III study in NSCLC is much larger and better controlled than the pilot study. Although recruitment was stopped before the target sample size of 756 patients was reached, the final sample size of 384 patients was sufficient for statistical analysis. In years 1, 3, and 5, the overall survival rate in the AE-941 group was 59%, 25%, and 14%, respectively. In the placebo group, overall survival rates at 1, 3, and 5 years were 61%, 21%, and 14%, respectively. Secondary endpoints also did not lead to a statistical benefit. This multicenter study included both academic and community clinics and was well controlled and designed.
As practitioners, it is important that we stay abreast of new information about natural ingredients that are thought to have anti-cancer effects. We should neither allow ourselves to be influenced by the mainstream press nor reject ideas until all the evidence has been evaluated. Shark cartilage is an example of a promising productin vitrothat simply hasn't proven successful in large clinical trials. Although it is still sold on the market, there is not enough evidence to justify its use and there is evidence directly refuting its use in NSCLC. Of course, the supplement also places an ecological burden on the shark population, which is a separate but legitimate concern given its widespread use. The National Cancer Institute offers one Comprehensive list of all clinical study data for the various shark cartilage products.
restrictions
AE-941 is a complex natural product, not a single active ingredient. The company claims it is standardized, although there is no methodology or component breakdown to ensure replication or even batch-to-batch consistency. No batch numbers were disclosed in the current study, so this is an unanswered question regarding the current study. The dose may not have been sufficient, although the dose used in the study, 240 ml/day, was the highest dose tested to date in a Phase I study. The tolerable upper dose has not been established. Finally, when administered orally, components of AE-941 can be broken down through digestion before entering the bloodstream. Since no blood parameters of the ingredients or other blood markers could be recorded, it is unclear whether AE-941 was adequately absorbed intact.
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