Delta tocotrienol has anti-neoplastic activity as demonstrated in several in-vitro and in-vivo investigations. The effect relies on inhibition of different pathways. It also has antiangiogenic activity, and an additive effect to bevacizumab may be expected. The present study was a phase II trial of bevacizumab combined with tocotrienol in chemotherapy refractory ovarian cancer. The study also included analysis of circulating tumor specific HOXA9 methylated DNA (HOXA9 meth-ctDNA) during treatment. The study included 23 patients. The rate of disease stabilization was 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high compared to the current literature. A division of the patients according to level of HOXA9 meth-ctDNA already after the first cycle of chemotherapy resulted in two groups of patients with different prognoses. Patients with an increasing level of HOXA9 methctDNA had a median PFS and OS of 1.4 and 4.3 months, respectively, compared to 7.8 and 12 months in the group with stable or decreasing levels. The combination of bevacizumab and tocotrienol is potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy holds important prognostic information.


Despite considerable progress in cancer management, recurrent ovarian cancer still represents a therapeutic challenge. Most ovarian cancer patients will recur within few years after the primary treatment, and although second and even third line chemotherapy is efficient, the majority of the patients eventually become chemotherapy resistant with no or only few treatment options, all without curative potential. Bevacizumab has been established as an integrated part of both first [1,2] and second line [3,4] treatment of ovarian cancer. The combination with chemotherapy has improved the treatment results, but still, the majority of patients will die from their disease. The situation calls for new approaches to resistant disease with the perspective of improved quality of life and prolonged life span. The toxicity of such treatment should be very low or non-existing. Tocotrienols are vitamin E analogues with several biological targets. A considerable literature [5–7], mainly on in-vitro experiments but also a few in-vivo studies, has indicated a clear effect on malignant cells with respect to proliferation and invasion. Several mechanisms and effects on different pathways have been suggested [8] among which inhibition of two important transcription factors NF-kβ and STAT3 rank high. The delta form is especially active in relation to malignancies. It suppresses the vascular endothelial growth factor (VEGF) and inhibits proliferation of endothelial cells resulting in reduced tube formation [9,10]. The angiogenic activity may be an essential part of its antineoplastic effect. Therefore, an additive effect to bevacizumab could at least in theory be expected, which motivated the present study. Aberrant methylation occurs in almost all malignant tumors and1 tumor specific methylated DNA (meth-ctDNA) can be measured in the plasma from patients with various tumors. Plasma meth-ctDNA has been approved by the FDA as a tool in colorectal cancer screening [11]. In ovarian cancer focus has also been on early detection and screening, but recently, HOXA9 meth-ctDNA has been suggested as a prognostic marker [12]. We have presented a study on BRCA 1/2 positive patients treated with the PARP inhibitor veliparib [13]. The results indicate a considerable prognostic importance of HOXA9 meth-ctDNA and a further study [14] holds promise as to early selection of responding patients
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