Delta Tocotrienol and Bevacizumab for Recurrent Ovarian Cancer

Our Dr. Kirsten West contributed a write up for the Natural Medicine Journal detailing a clinical trial to assess if the combination of delta tocotrienol and bevacizumab delays the progression of multi-resistant ovarian cancer. Learn how the results show that multiple therapeutic actions and the low toxicity of delta tocotrienol demonstrate synergistic effects with bevacizumab in ovarian cancer.

Study: Delta Tocotrienol and Bevacizumab for Recurrent Ovarian Cancer

Reference

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.

Objective

To assess if the combination of delta tocotrienol and bevacizumab delays the progression of multiresistant ovarian cancer.

Design

Phase II, nonrandomized, single-arm, open-label clinical trial

Participants

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.

Outcome Measures

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.

Key Findings

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.

Practice Implications

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.

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

Read the full study: Delta Tocotrienol and Bevacizumab for Recurrent Ovarian Cancer