Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer

Abstract

PurposePreclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC).MethodsPatients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.ResultsAdenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups.ConclusionFolic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.

Safety and efficacy of vitamin B in cancer treatments: A systematic review

“…Included studies examined Vitamin B1 ( n = 1), 17 Vitamin B3 ( n = 2), 17,18 Vitamin B6 ( n = 16), 17–32 Vitamin B9 ( n = 15), 17–23,28,30–36 Vitamin B12 ( n = 16), 17–23,28,30–33,35,36 and Vitamin B Complex ( n = 1). 37 Details of the included studies and results can be found in Tables 2 and 3.…”

“…The findings are as follows B9 and B12 showed a higher risk of colorectal cancer HR: 1.77; 95% CI, 1.08–2.90 p = 0.02, as well as a higher risk of overall cancer HR: 1.25; 95% CI, 1.00–1.53 p = 0.05. 33 Van Zweeden et al, 35 studied the combination effect of both B9 and B12 on advanced esophagogastric cancer (AEGC) concluding that combined B9 and B12 had no effect on OS or TTP ( p = 0.9). Singer et al 20 found that maternal intake of one-carbon metabolism nutrients from food or supplements correlated to a lower occurrence of childhood acute lymphoblastic leukemia (OR for one-unit change in the principal component = 0.91, CI: 0.84–0.99).…”

“…The studies consisted of 16 quantitative non-randomized trials and nine quantitative randomized controlled trials. Included studies examined Vitamin B1 (n = 1), 17 Vitamin B3 (n = 2), 17,18 Vitamin B6 (n = 16), [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Vitamin B9 (n = 15), [17][18][19][20][21][22][23]28,[30][31][32][33][34][35][36] Vitamin B12 (n = 16), [17][18][19][20][21][22][23]28,[30][31][32][33]35,36 and Vitamin B Complex (n = 1). 37 Details of the included studies and results can be found in Tables…”

Novel Implications of MicroRNAs, Long Non-coding RNAs and Circular RNAs in Drug Resistance of Esophageal Cancer

“…Although treatment options are limited for patients with unresectable, locally advanced, or metastatic esophageal cancer, a portion of patients could benefit from the comprehensive treatment of chemotherapy, targeted therapy and immunotherapy with immune checkpoint inhibitors ( Eltweri et al, 2019 ; Kojima et al, 2020 ; Lopez et al, 2020 ; Stroes et al, 2020 ). The commonly used chemotherapeutic agents in clinics include platinum drugs, 5-fluorouracil (5-FU), adriamycin (ADM), paclitaxel (PTX), irinotecan, gemcitabine (GEM), and vinorelbine ( Liu S. L. et al, 2015 ; Wang Y. S. et al, 2016 ; Tin et al, 2018 ; van Zweeden et al, 2018 ; Ni et al, 2020 ). Molecular targeted therapy drugs include anti-HER2 monoclonal antibodies (trastuzumab and pertuzumab), oral tyrosine kinase inhibitors (TKIs) targeting HER-1/HER-2 (lapatinib), anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (ramucirumab) and anti-EGFR monoclonal antibody (panitumumab) ( Press et al, 2017 ; Shepard et al, 2017 ; Chakrabarti et al, 2018 ; Guo et al, 2018 ; Yamaguchi et al, 2018 ; De Vita et al, 2019 ; Hassan et al, 2019 ; Rogers et al, 2019 ; Wagner et al, 2019 ; Stroes et al, 2020 ).…”

Combined modality treatment of stage II-III esophageal cancer: a single center experience

“…Кроме того, с 2010 года начали появляться результаты применения гемцитабина (от 1000 мг/м 2 до 1250 мг/м 2 ) в различных комбинациях при РП. При этом было получено улучшение общей выживаемости [3,18] Следует отметить, что до начала лечения в основной группе у 30 (85,7%) и в контрольной группе у 29 (82,8%) больных имелась дисфагия различной степени выраженности. При дисфагии III-IV степени в основной группе у 16 (45,7%) и в контрольной группе у 14 (40%) больных проводилось парентеральное питание, состав и объем которого зависел от состояния больного и лабораторных показателей.…”