Comparison of folate derivate levels in mucosa and tumor tissue in the course of antifolate treatment with pemetrexed.

Abstract

10612 Background: THF (tetrahydrofolate), methyl-THF and methylene-THF are cornerstones for viability of mucosa with different functions in the cell cycle. Understanding the tumor growth and the role of reduced folates is essential in the understanding of mechanisms that occur during chemotherapy with pemetrexed and folate supplementation. Methods: 37 patients (pts) with operable nonmetastatic rectal adenocarcinoma were enrolled. Pemetrexed 500 mg/m2 was administered every 3 weeks, during 3 cycles with standard comedication (vitamin B12, folic acid, and dexamethasone). Biopsies of tumor and adjacent mucosa were taken before the patient received vitamin supplementation, after supplementation but before antifolate therapy and at surgery. A LC-MS/MS method was used for the determination of THF, methylene-THF and methyl-THF levels. Results: See Table. All levels of the three folate derivates increased significantly after the start of the supplementation, in mucosa as well as in tumor tissue. Mean THF and methylene-THF levels were significantly higher in tumor compared with mucosa at baseline, after folate supplementation and at surgery after 3 cycles of pemetrexed. Conclusions: In a population of 37 pts with rectal cancer, there was a strong and consistent significant difference observed for reduced folates between tumor and mucosa. High tumor tissue levels of reduced folates need further exploration to better understand the biological basis to optimize the treatment in rectal cancer and in other tumor entities. Baseline After supplementation At surgery THF a 463/584 620/901 704/906 b 123 (294) 292 (408) 202 (459) c p = 0.006 p ≤ 0.001 p = 0.012 d 36/37 35/35 37/37 Methyl-THF a 352/436 640/903 639/1065 b 84 (227) 263 (352) 426 (585) c p = 0.051 p ≤ 0.001 p ≤ 0.001 d 37/37 36/36 37/37 Methylene-THF a 830/1,018 1,405/2,067 1,302/1,871 b 188 (718) 662 (1,272) 568 (1,352) c p = 0.018 p ≤ 0.001 p = 0.004 d 37/37 36/36 37/37 a = mean levels mucosa/tumor (M/T) (pmol/g); b = Difference T/M, mean (SD); c = p value*; d= number of pts, M/T. * Wilcoxon signed rank test was used for pairwise comparison T-M, testing whether mean difference is zero. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly