Thomsen CB, Andersen RF, Steffensen KD, Adimi P, Jakobsen A. Delta tocotrienol in recurrent ovarian cancer. A phase II trial. Pharmacol Res. 2019;141:392-396.
To assess if the combination of delta tocotrienol and bevacizumab delays the progression of multiresistant ovarian cancer.
Phase II, nonrandomized, single-arm, open-label clinical trial
The study included 23 women with advanced-stage, histologically verified endothelial fallopian or peritoneal ovarian cancer that had progressed despite treatment with at least 2 (median of 4) different cytostatic regimens. All patients were platinum-resistant, and more than half had previously progressed while on bevacizumab. Most participants had stage III disease at the time of diagnosis and serous histopathology was the dominant type. All participants were >18 years, had a performance status of 0-2, and had adequate organ function.
Study Medication and Dosage
Patients received intravenous bevacizumab (Avastin) 10 mg/kg every 3 weeks and tocotrienol capsules, 90% delta tocotrienol, by American Red River Nutrition (USA), 300 mg 3 times a day throughout the course of the trial.
In patients with measurable disease, chest and abdominal CT scans were performed every 3 cycles. In those patients with nonmeasurable disease, serum cancer antigen (CA)-125 levels were assessed every 3 cycles. Patients were only eligible for response evaluation if progression had not occurred on previous evaluation. The primary endpoint was the rate of disease control. Secondary endpoints included quality of life (QoL; evaluated by EORTC QLQ-C30), safety, progression-free survival (PFS) and overall survival (OS). Quality of life scores were measured before start of treatment, at the first response evaluation, and again at progression.
In patients with chemotherapy refractory ovarian cancer, the addition of tocotrienol to bevacizumab produced a significant benefit. The study occurred over the course of 34 months (March 2015-January 2018). The median number of treatment cycles was 6, and 20% of patients were treated for more than 12 months. Adverse events/toxicity—consisting of gastrointestinal toxicity, rectal bleeding, and increased hypertension—resulted in 3 patients discontinuing treatment and were attributed to bevacizumab. Quality of life measurements were stable throughout the trial and were accompanied by a notable drop in disease progression. Seventy percent (14/20) of the study participants experienced disease control at some point during the study. Half were experiencing control at 6 months from baseline. (A previous Phase II trial assessing bevacizumab alone resulted in 31% of participants with stable disease at 6 months.)1
In this group of heavily pretreated women, the average PFS was 6.9 months and the average OS was 10.9 months. Twenty percent were alive without progression for more than 1 year, and OS at 25 months was 25%. These results were irrespective of previous bevacizumab treatment.
In 2018, there were approximately 22,240 new diagnoses of ovarian cancer and 14,070 deaths due to this malignancy in the United States.2 Due to the absence of symptomology in the early stages, most ovarian cancers are diagnosed at stage III.2 At stage III, the disease is considered advanced with dissemination throughout the abdomen and involvement of lymph nodes. Due to late-stage diagnoses, ovarian cancer commonly recurs and requires cytotoxic treatment, eventually becoming refractory to all approved agents. The 5-year survival rate for women with stage III disease is 47%.2 The challenge, once approved therapies have been exhausted, is to identify additional therapies that confer benefit (in both PFS and OS) while not diminishing QoL.
In patients with heavily pretreated, advanced ovarian cancer who opt for further treatment, current studies indicate a median PFS of 2-4 months and a median OS of 5-7 months.3 Given the results of the study currently under review, in which PFS was 6.9 months and OS was 10.9 months, it appears that the use of tocotrienol in combination with bevacizumab may be a reasonable option for these women.
The lead investigator in this study, Caroline Thomsen, MD, a medical oncologist at Vejle Hospital in Denmark, believes the effects of delta tocotrienol rely not only on its antiangiogenic activity but also on inhibition of additional mechanisms specific to aberrant cellular growth.
Bevacizumab was approved by the US Food and Drug Administration (FDA) in 2018 for post-surgical treatment of ovarian cancer.4 Bevacizumab is a recombinant monoclonal antibody directed against VEGF (vascular endothelial growth factor), a pro-angiogenic cytokine. Its approval as a frontline therapy was based on studies such as a 2018 double-blind, multi-center study by Chikazawa et al, which showed a 38% reduction in disease progression.4 It has also been approved as primary treatment in patients who have become resistant to first-line therapy with platinum-based agents, as it has been shown to significantly improve PFS and OS.4-6
Vascular endothelial growth factor contributes to the pathogenesis of ovarian cancer5 by promoting angiogenesis, thereby driving endothelial cell survival, proliferation, and migration. In doing so, VEGF also increases vascular permeability. This increased permeability contributes to the development of peritoneal carcinomatosis and malignant ascites—2 common pathologic processes seen in late stage ovarian cancers.7 Therefore, it is not surprising that bevacizumab can act to inhibit tumor growth and decrease symptoms associated with VEGF production. Improvements in PFS and OS from bevacizumab are also not surprising, given VEGF levels are inversely related to survival.8
Similar to bevacizumab, tocotrienols have been shown to inhibit VEGF and may offer a therapeutic advantage in the treatment of ovarian cancer.9,10 VEGF suppression is only one of the several actions of tocotrienols.11-13
Tocotrienols are part of the vitamin E family. This family consists of 8 vitamers (separate but related naturally occurring vitamin molecules): 4 tocopherols (alpha, beta, gamma, and delta) and 4 tocotrienols (alpha, beta, gamma, and delta).14 Most previous studies have focused on alpha tocopherol.15 More recent studies now show that tocotrienols may have greater health benefits.12 High amounts of alpha tocopherol (25%-50% of total vitamin E) may actually interfere with the actions of tocotrienols via inhibition of tocotrienol absorption, inhibition of cytotoxic effect, and induction of tocotrienol breakdown.16-19 Although tocopherols are potent antioxidants, they have not been shown to decrease aberrant cell growth.15 Large clinical trials have even implicated an equivocal and possibly harmful effect when used as a single, high-dose tocopherol.20-22
Most prior studies have focused on the use of tocotrienols in cardiovascular health. These studies have shown tocotrienols to have significant cardiovascular benefit via suppression of HMG-CoA reductase, inhibition of lipid peroxidation, inhibition of reactive oxygen species production, regulation of heat shock protein expression, inhibition of platelet aggregation, and improved nitric oxide synthase activity.23-30
More recent in vitro/in vivo studies have offered insight into the possible role of tocotrienols in cancer chemoprevention and treatment. These anticarcinogenic mechanisms include: down regulation and/or degradation of HMG-CoA reductase (as previously noted), stimulation of caspase-3 apoptotic pathways, and inhibition of several common pathways, such as angiogenesis (VEGF), inflammation (nuclear factor [NF]-kB, cyclooxygenase [COX]-2) and signal transduction (STAT3).9,31-35 Such anticarcinogenic mechanisms are prompting further clinical study.
The lead investigator in this study, Caroline Thomsen, MD, a medical oncologist at Vejle Hospital in Denmark, believes the effects of delta tocotrienol rely not only on its anti-angiogenic activity but also on inhibition of additional mechanisms specific to aberrant cellular growth. As her outcomes above suggest, delta tocotrienol may have some synergism with bevacizumab. Whether this activity is due to the suppression of VEGF alone remains to be clarified. The effects are likely multiple. These multiple actions may provide not only synergism with bevacizumab but also regulation via alternate mechanisms, as demonstrated by experimental studies.
Two additional clinical trials sought to assess the activity and therapeutic efficacy of delta tocotrienol in the management of cancer.
The first was a 2015 study by Springett et al on 25 patients with pancreatic cancer or high-risk precancerous pancreatic tumors who were scheduled for curative resection.36 Per study results, once levels of delta tocotrienol reached a certain blood level, anticancer activity was significant, as measured via caspase-3 levels in resected tumor tissue. A dose of 800 mg delta tocotrienol yielded the highest response rate when compared to higher and lower doses. This response rate was 80%. The dose of 800 mg delta tocotrienol is similar to the dose (900 mg/day) used by Thomson et al in the current study under review .
A 2010 clinical trial by Nesaretnam et al evaluated the use of delta tocotrienol in 240 women with early stage breast cancer.37 Only 200 mg of delta tocotrienol was given alongside 20 mg of tamoxifen daily for 5 years. The tocotrienol and tamoxifen combination did not show any survival advantage or disadvantage.
Additional clinical trials on the anticancer effects of tocotrienols are limited. As noted, most clinical trials to date have studied the anticancer effects of Vitamin E (preparations containing tocopherols and tocotrienols) and several papers on “vitamin E” do not stipulate what form(s) of vitamin E were used. Perhaps, given the emerging data, the focus best rests on the shoulders of tocotrienols and, specifically, those in the delta form.
The dose and timing of tocotrienol intake may make a difference in its efficacy. In 2001, Yap et al found that the compounds are best taken with meals to increase absorption from the gastrointestinal tract.38 Furthermore, it is recommended that tocotrienols are best taken approximately 6 hours away from any tocopherol supplement given the possible interference referenced above. In the current study (of women with ovarian cancer) and the previously mentioned trial by Springett et al (of men with pancreatic cancer), the clinically effective presurgical dose of tocotrienol was 800-900 mg per day.36 Given that most delta tocotrienol supplements sold today contain only 70-100 mg of delta tocotrienol per capsule, the capsule load (8-9/day) may be an obstacle for many patients.
This current study by Thomsen et al, while promising, is limited. The number of participants was small, it was phase II, and nonrandomized. Although the effects of delta tocotrienol seem to be synergistic with bevacizumab, we do not have evidence to support extrapolating this action with other cytotoxic and/or cytostatic agents. However, given the low toxicity and well-tolerated high doses, further research in delta tocotrienol is an intriguing, nontoxic option for patients suffering the sequela of previous cytotoxic therapies. This is especially true in women with chemo-refractory ovarian cancer, and may coincide with other multi-refractory malignancies.
These results from Thomsen et al point to the emerging, multiple therapeutic actions and low toxicity of delta tocotrienol and demonstrate synergistic effects with bevacizumab in ovarian cancer. Further studies of delta tocotrienol to verify this result and determine if there is synergism with other agents used in cancer treatment are warranted.
- Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180-5186.
- Torre LA, Trabert B, DeSantis CE, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284-296.
- Oronsky B, Ray CM, Spira AI, Trepel JB, Carter CA, Cottrill HM. A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer. Med Oncol. 2017;34(6):103.
- Chikazawa K, Netsu S, Kuwata T, Konno R. Bevacizumab improves overall survival in platinum refractory ovarian cancer patients: a retrospective study. Taiwan J Obstet Gynecol. 2018;57(6):819-824.
- Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496.
- Emile G, Chauvenet L, Tigaud JM, Chidiac J, Pujade Lauraine E, Alexandre J. A clinical experience of single agent bevacizumab in relapsing ovarian cancer. Gynecol Oncol. 2013;129(3):459-462.
- Matsuoka A, Mizumoto Y, Ono M, et al. A novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization [published online ahead of print June 14, 2019]. Cancer Sci.
- Shen W, Li HL, Liu L, Cheng JX. Expression levels of PTEN, HIF-1α, and VEGF as prognostic factors in ovarian cancer. Eur Rev Med Pharmacol Sci. 2017;21(11):2596-2603.
- Miyazawa T, Shibata A, Nakagawa K, Tsuzuki T. Anti-angiogenic function of tocotrienol. Asia Pac J Clin Nutr. 2008;17 Suppl 1:253-256.
- Weng-Yew W, Selvaduray KR, Ming CH, Nesaretnam K. Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer. 2009;61(3):367-373.
- Kannappan R, Gupta SC, Kim JH, Aggarwal BB. Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes Nutr. 2012;7(1):43-52.
- Viola V, Pilolli F, Piroddi M, et al. Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E. Genes Nutr. 2012;7(1):29-41.
- Ling MT, Luk SU, Al-Ejeh F, Khanna KK. Tocotrienol as a potential anticancer agent. Carcinogenesis. 2012;33(2):233-239.
- Jiang Q. Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms. IUBMB Life. 2019;71(4):495-506.
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