Delta Tocotrienol Improves Survival in Advanced Ovarian Cancer

AnnattoSupplementation with delta-tocotrienol, a form of vitamin E derived from annatto seeds, can delay progression of ovarian cancer and improve overall survival when combined with anti-angiogenic drug therapy, according to a recent study.

“Delta-tocotrienol has anti-neoplastic activity, as demonstrated in several in vitro and in vivo investigations,” notes Caroline Brenner Thomsen, an oncologist at the Vejle Hospital, Denmark. “The effect relies on inhibition of different pathways. It also has antiangiogenic activity.”

Brenner Thomsen and her colleagues studied the effect of delta-tocotrienol supplementation at dose levels of 300 mg, thrice daily, in combination with bevacizumab in a small cohort of 23 women with refractory ovarian cancer.

Despite the considerable advances in treatment of other types of cancer, recurrent ovarian cancer still represents a major therapeutic challenge. Most ovarian cancers will recur within a few years after primary treatment. Although second and even third line chemotherapy may confer some benefit, the majority of patients eventually become chemotherapy-resistant.

Bevacizumab (Avastin), a monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A), is a key component of both first- and second-line conventional protocols for ovarian cancer. In combination with older chemo regimens, it improves outcomes somewhat. But like other drugs, it is hardly curative, and the majority of women with ovarian cancer still die from the disease.

Mitigating Proliferation

Tocotrienols are vitamin E analogues with multiple physiological targets. In the cancer context, they’ve been shown in vitro to mitigate proliferation and invasiveness of neoplastic cells. They appear to inhibit two important transcription factors: NF-κβ and STAT3. 

The delta form used in this Danish study appears to be the most active of the various tocotrienols in terms of its anti-neoplastic effects. It suppresses VEGF and can slow the proliferation of endothelial cells.

This constellation of effects has led researchers to suggest that delta-tocotrienol might provide additive benefits when combined with anti-angiogenic drugs like bevacizumab.

The Danish researchers recruited 23 women with histologically verified fallopian or peritoneal ovarian cancer, which progressed despite treatment with at least two different chemotherapeutic regimens. Most had stage III disease at the time of diagnosis.

All were treated with intravenous bevacizumab, 10 mg/kg, every three weeks, as well as capsules containing 90% delta-tocotrienol, 300 mg, thrice daily. The patients continued on treatment until there were clear signs of tumor progression, symptoms of grade 3 bevacizumab toxicity, or they requested cessation of treatment.  Three of the patients discontinued owing to bevacizumab-related adverse effects.

Based on chest and abdominal CT scans and standardized clinical evaluation scales (GCIC CA12 and RECIST 1.1), the investigators concluded that, “the rate of disease stabilization was 70%, with very low toxicity.”

Prolonged Survival

Median progression-free survival was 6.9 months, and median overall survival was 10.9 months, “which is rather high compared to the current literature.” After 6 months of treatment, 50% of the patients were considered “disease-controlled.” Median overall survival was 10.9 months, and 25% of the women were still alive at 24 months (Thomsen CB, et al. Pharmacol Res. 2019).

Though these statistics may seem modest, they are actually pretty good for a highly aggressive, chemo-resistant form of cancer like this.

The authors posit an additive effect from the tocotrienol supplements, noting that in phase II trials of bevacizumab alone, only 25% of patients show disease control after 12 weeks. At best, bevacizumab alone gives a 31% disease control rate after 6 months of treatment.

“The present study suggests that a prolonged lifespan can be reached without negative influence on quality of life,” Brenner ThomsenTocopherols Tocotrienols and colleagues write.  “It could be claimed that the prolongation is based on bevacizumab alone, but the progression-free survival was only 4.2 months and the overall survival was 6.7 months in our previous trial on single agent bevacizumab in the same category of patients.”

The Danish team attributed the observed benefit of delta-tocotrienol to its antiangiogenic effects, which have been repeatedly demonstrated in cell culture and animal studies. They stress, however, that this property is unique to tocotrienol and not seen with any of the tocopherols (Shibata A, et al. J Nutrit Biochem. 2015).

Traptol–the tocotrienol supplement used in the study—is a special product of exceptional purity. It contains 90% delta tocotrienol, “which may explain the clinical effect in our study.” The findings, therefore, may not be generalizable to other, lower-concentration tocotrienol supplements.

“The dose given was high compared to conventional use of tocotrienol, but it was well tolerated over several months and in agreement with a phase I study in which the dose was increased to 3,200 mg daily for six weeks” (Springett GM, et al. Lancet EbioMedicine. 2015).

Seeing Red

The Traptol formula is produced by American River Nutrition, a Massachusetts-based nutraceutical manufacturer specializing in tocotrienols. It is available in the US as DeltaGold.

The general term “Vitamin E” represents eight distinct compounds: four tocopherols and four tocotrienols, each with distinct structures and biological properties. While much of the legacy research on Vitamin E was done with alpha-tocopherol, more recent studies have suggested that the tocotrienols—especially delta- and gamma-tocotrienol—provide the real health benefits of vitamin E, and that the more commonly used alpha-tocopherol may, in fact, impede the benefits of the tocotrienols.

Tocotrienols are naturally-occurring compounds found in Palm, Rice, and Annatto. Of these three sources, only the bright red seeds of the Annatto plant (aka Achiote) produce tocotrienols with virtually no trace of any tocopherols.

Annatto (Bixa Orellana) is native to Central and South America, and the vivid seeds are widely used in these regions as a spice and a food coloring.

BarrieTan minBarrie Tan, PhD, formerly UMass Amherst biochemist with a life-long interest in Vitamin E compounds, became interested in Annatto while on a trip to South America in the late 1990s. The deep red color of the tree’s seeds indicated that they were rich in carotenoids, which are generally very labile compounds easily degraded by oxidation. Annatto seeds retain their bright color despite exposure to sunlight and heat, an observation that intrigued Tan.

Something, he reasoned, was protecting the Annatto carotenoids. He undertook detailed analysis of the chemical profile of these seeds: the key protective molecule turned out to be delta-tocotrienol. Tan contends that Annatto seeds are the only naturally occurring source of nearly pure (90%) delta-tocotrienol without any tocopherol.

These discoveries led Tan to establish American River Nutrition, with the goal of bringing naturally-sourced, US-manufactured delta-tocotrienol supplements into the US and international natural products markets.

The Brenner Thomsen study is the first to look at delta-tocotrienol in the treatment of ovarian cancer. But it is not the first time that researchers have explored the potential of tocotrienols in the cancer context.

A previous study involving 240 women with early stage breast cancer–a disease with a generally high survival rate–did not show any survival advantage from adding tocotrienol to a tamoxifen regimen (Nesaretnam K, et al. Breast Cancer Res. 2010).

But given the emerging discoveries about the ways in which tocotrienols down-regulate transcription factors associated with tumor proliferation, as well as inflammatory signals—including neurotrophic factor κB (NF-Β) and cyclooxygenase (COX)-2—there are reasons to believe that these antioxidant compounds could be useful adjuncts in the treatment of other forms of cancer.

On July 25, at 8pm Eastern, you’ll have an opportunity to learn more about tocotrienols, and their role in human health, as Holistic Primary Care hosts a special webinar with Dr. Tan. The program is sponsored by American River Nutrition and Designs for Health.



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