Short summary

Colorectal cancer is a disease with significant mobidity and mortality. The overall 5-year survival rate is 55-60%.

The aim of the present study is to compare the effect and toxicity of standard chemotherapy and bevacizumab with the same regimen supplemented with tocotrienol in metastatic colorectal cancer. Tocotrienol is a vitamin E derivat.

Rationale

Colorectal cancer is a common cancer with around 4900 new cases diagnosed per year in Denmark. Twenty-five percent have metastatic disease at the time of diagnosis and of the remaining, 50% will later develop incurable disease. Metastatic colorectal cancer (CRC) patients have poor outcomes with a 5-year survival rate of 13% and a median overall survival of six months without treatment. 

Metastatic colorectal cancer represents a therapeutic challenge. For patients with non-resectable metastatic colorectal cancer (mCRC) the primary goal is symptom relief, better quality of life and prolongation of survival. The standard treatment is a combination of two drugs with potential benefit of adding biologically targeted treatment. Choice of treatment regimen depends on the patient´s performance status and previous treatment.

Angiogenesis is essential in tumor development, growth, and dissemination. Targeting this biological process represents a common treatment approach in mCRC. Bevacizumab is a monoclonal antibody that binds to the vascular endothelial growth factor A (VEGF-A) resulting in decreased angiogenesis. Added to chemotherapy it provides modest benefit depending on combination and the number of previous treatments. Bevacizumab has shown survival benefits when added to chemotherapy in patients with mCRC.

Tocotrienol is a derivate of the natural vitamin E. Delta-isoform of tocotrienol has several biological effects including effect on malignant cells, which has been shown in several studies. In vivo experiments in different animal models have shown that delta-tocotrienol inhibits angiogenesis and tumor growth resulting in prolonged survival. It has an additive effect on cytostatic as summarized in a recent review based on the available in vitro, in vivo and clinical studies. Furthermore, it suppresses VEGF and inhibits proliferation of endothelial cells resulting in reduced tube formation. The toxicity of tocotrienol is low or non-existing.

Circulating tumor specific DNA (ctDNA) as a "liquid biopsy" has recently gained considerable interest as a marker of potential clinical value holding promise of treatment monitoring. Aberrant methylation occurs in almost all malignant tumors and tumor specific methylated DNA can be measured in the plasma from patients with various tumors. Several papers have shown that circulating methylated DNA holds prognostic information, but there are no major studies dealing with treatment monitoring or follow-up in metastatic disease.

Natural killer (NK) cells are essential in the biological fight against cancer and intracellular pathogens. Their level of activity has in many settings been used as a biomarker for a functional immune response.

As the development and progression of CRC are known to be affected by the immune system, cell subsets such as T-cells, NK cells and NKT cells are considered interesting candidates for clinical biomarker research.

A study aiming to characterize the immunophenotypes of circulating T-cells, NK cells, and NKT-like cells in patients with CRC highlights the potential use of the analyses. Profound differences were demonstrated in subsets distribution and immunophenotype of peripheral blood mononuclear cell samples in CRC patients compared to healthy donors.

The present study is a double blind, randomized phase II trial. The intervention group receives chemotherapy and bevacizumab plus tocotrienol, whereas the control group receives chemotherapy and bevacizumab plus placebo.

Chemotherapy with either FOLFOX or capecitabine/5-FU is planned for a period of maximum six months, until progression or unacceptable toxicity. Patients experiencing unacceptable side effects of FOLFOX can be offered treatment with capecitabine or 5-FU as an alternative. If chemotherapy treatment is withdrawn based on toxicity or patient wish, the patient can continue with bevacizumab in combination with tocotrienol/placebo up to a total of six months as planned.

Description of the cohort

Includes patients diagnosed with metastatic colorectal cancer, who are offered palliative chemotherapy with either FOLFOX or Capecitabine plus Bevacizumab at the Department of Oncology, Vejle Hospital.

Data and biological material

We collect blood samples.

Clinical and demographic data.

Collaborating researchers and departments

Department of Oncology, Vejle Hospital

• Associate professor, MD, PhD, Torben Frøstrup Hansen (Sponsor)
• Associate professor, MD, PhD, Lars Henrik Jensen

Department of Clinical Biochemistry, Vejle Hospital

• Moleculalar biologist, PhD, Line Nederby
• Molecular biologist, PhD, Rikke Fredslund Andersen