CISTRON - Impact of stereotactic body radiation therapy on the coagulation system in patients with non-small cell lung cancer
The risk of thromboembolism is elevated in lung cancer patients. The present project will include 100 patients and investigate whether stereotactic body radiation therapy (SBRT) further increases the risk of thromboembolic disease in lung cancer patients.
If coagulation is activated by SBRT, this study could form the basis of new clinical trials investigating whether lung cancer patients may benefit from thromboprophylaxis during and after stereotactic body radiation therapy.
The risk of thromboembolic disease is substantially increased in cancer patients compared to the general population. Lung cancer is one of the most thrombogenic cancers, with thromboembolism occurring in up to 14% of the patients. Thromboembolism prompts a significant clinical and economic challenge since thromboembolic events have great impact on both mortality and on quality of life in survivors.
Previous studies indicate that the cancer itself poses an activation of the coagulation system. However, recent studies on coagulation in operable lung cancer patients showed that coagulation in patients with primary lung cancer suitable for surgery did not differ substantially from healthy individuals. It is well-known that both chemotherapy, hormone therapy and immunotherapy increases the risk of thromboembolism, but knowledge on the effect of radiation therapy is sparse.
Studies on cell lines and in animal models suggest that radiotherapy may activate coagulation. However, a recent study including women receiving post-operative radiotherapy after breast cancer surgery demonstrates that coagulation is unaffected by radiotherapy. But it is yet unknown, whether high dose radiotherapy might activate coagulation in patients with active cancer.
Stereotactic body radiation therapy (SBRT) is high-dose radiotherapy delivered in few fractions to the tumour. SBRT is offered to inoperable patients with localized non-small cell lung cancer and secures the same local control of the tumour compared to surgery. As a result, SBRT is an alternative treatment offered to medically inoperable patients. Since approximately 50% of lung cancers are diagnosed in patients aged 70 years or older, patients are often inoperable due to comorbidity, and are consequently treated with SBRT. Age is known to be an independent risk factor for thromboembolism, which further increases the risk of thromboembolic events in these patients.
As a result, lung cancer patients treated with SBRT have several thromboembolic risk factors beyond cancer, such as high age and substantial comorbidity. Consequently, SBRT might adversely affect coagulation in these high-risk patients and thereby further increase their thromboembolic risk.
Data also indicates that many of the lung cancer patients treated with SBRT die of other causes than the lung cancer. This may be due to a thromboembolism. Only little is known about how radiation therapy influences older and/or comorbid lung cancer patients. This heterogenic group has many risk factors for thromboembolism and might be a subgroup with a considerable higher risk of thromboembolism than the average cancer patient. This knowledge gap might be addressed by the Khorana score. The Khorana score is a validated screening tool for risk of thrombosis in cancer patients prior to chemotherapy and it might turn out to be a valid tool for screening lung cancer patients at baseline and identifying those patients at high risk of developing thromboembolism prior to SBRT.
Therefore better characterization of real life patients including their risk of developing thromboembolic event will hopefully lead to optimized care for the individual patient with for example thromboprophylaxis medicine. The present project investigates whether SBRT further increases the risk of thromboembolic disease in lung cancer patients.
• To identify possible changes in the coagulation system during stereotactic body radiation therapy in lung cancer patients
• To describe the activity of the coagulation system in lung cancer patients compared with healthy individuals
Description of the cohort
This is a prospective study of 100 consecutively included lung cancer patients receiving stereotactic body radiation therapy at the Department of Oncology, Odense University Hospital. As standard treatment, which is considered for best practice, the patients receive:
a) 66 Gy/ 3 fractions (F) (new primary peripheral lung cancer), or
b) 50 Gy/ 5 F (new primary central lung cancer), or
c) 45 Gy/ 3 F (peripheral lung cancer relapse after initial surgery or stereotactic body radiation therapy).
Data on healthy individuals for comparison are already collected
Data and biological material
Blood sampling will be performed:
• prior to start of stereotactic body radiation therapy
• immediately after stereotactic body radiation therapy completion
• four to six weeks after completing stereotactic body radiation therapy
To describe the coagulation, the below mentioned parameters will be analyzed:
Primary haemostasis: Platelet count, immature platelet count, immature platelet fraction, platelet function (Multiplate Analyzer; ADP, collagen, TRAP), P-selectin.
Secondary haemostasis: APTT, INR, fibrinogen, coagulation factor VIII, Von Willebrand factor (antigen), thrombin generation, thrombin-antithrombin complex.
Fibrinolysis: Clot lysis (in-house assay)
Endothelial markers: Syndecan-1, sE-selectin, soluble thrombomodulin
Additional analyses: Haemoglobin, leucocyte count, D-dimer, C-reactive protein
And blood for a Biobank for future research.
Collaborating researchers and departments
Department of Oncology, Odense University Hospital
- Senior Consultant Stefan Starup Jeppesen, PhD, MD
- Professor Olfred Hansen, PhD, MD
Department of Clinical Biochemistry and Pharmacology, Odense University Hosital
- Associate Professor Pernille Vinholt, PhD, MD
Department of Clinical Biochemistry, Aarhus University Hospital
- Professor Anne-Mette Hvas, PhD, MD
- Consultant Johanne Andersen Højbjerg, PhD fellow, MD