1. Department of Surgery, University Hospital of Ioannina, Greece;
2. Department of Nephrology, University Hospital of Ioannina, Greece;
3. Unit of Molecular Biology of the Haematology Laboratory, University Hospital of Ioannina, Greece.
#The first two authors (MM and PK) are co-first authors, as they have contributed equally to this study.
Background/Purpose: In colon cancer (CC) patients preoperative (pre-op) levels of VEGF-A165 (VEGF) is a strong predictor for disease recurrence. Elevated postoperative (post-op) VEGF levels could have undesirable effects by enhancing tumor growth and metastasis formation. It has been suggested that thromboprophylaxis with a Low Molecular Weight Heparin (LMWH) in surgical cancer patients, further to thromboembolic protection, may exert some anti-neoplastic properties, as well. The aim of our study was to assess the potential impact of the LMWH Tinzaparin (Innohep® - Leo Pharma, Copenhagen, Denmark), given at different doses and for different perioperative (peri-op) periods, upon the post-op variability of serum VEGF levels in surgical CC patients.
Methods: A total of 54 consecutive CC patients who underwent a curative resection were randomized in four groups according to their peri-op thromboprophylaxis scheme, which was based on administrating Tinzaparin in different doses and at different periods, as follows: group I: 3,500 IU for 10 days, group II: 3,500 IU for 30 days, group III: 4,500 IU for 10 days and group IV: 4,500 IU for 30 days. Serum VEGF concentrations were evaluated on the pre-op day (Day 0) and on the 10th and 30th post-op days (Day 10 and Day 30, respectively). For statistical analyses the mixed design ANOVA was used. P < 0.05 was considered significant.
Results: On Day 0, VEGF didn't differ between groups I, II, III and IV (p>0.05, for every comparison). On Day 10, VEGF was increased in all groups. Between Day 10 and Day 30, VEGF remained stable in groups I (p=0.031) and II (p=1.000) and increased significantly in group III (p=0.005). On the contrary, VEGF decreased significantly in group IV (p<0.001). The most remarkable finding was observed when we compared VEGF between Day 0 and Day 30: while in groups I, II and III, VEGF remained significantly higher compared to Day 0 (p<0.001, p=0.041 and p<0.001, respectively), on the contrary, in group IV (extended-duration with the highest dose of 4,500 IU of tinzaparin) it was comparable to Day 0 (p=1.000).
Conclusions: In surgical CC patients only the recommended thromboprophylaxis scheme with the highest prophylactic dose of Tinzaparin (4,500 IU) for extended-duration (30 days) normalizes VEGF levels at the end of the first post-op month by reducing them to the pre-op levels.
Keywords: colon cancer, tinzaparin, thromboprophylaxis, VEGF, angiogenesis.