Page 67 - Demo

Vitamin B12 and folic acid in advanced oesophageal and gastric cancer654IntroductionEsophagogastric cancer is one of the most common malignancies of the gastrointestinal tract worldwide. These cancers encompass malignant epithelial neoplasms located in all regions of the esophagus and stomach irrespective of the histological type. In the majority of cases, the malignancies are adenocarcinomas (AC) or squamous cell carcinomas (SCC). The incidence of SCC has largely remained constant over time, while the incidence of AC has increased[1]. Treatment for metastatic disease is palliative and frequently consists of combination chemotherapy and/or radiotherapy. The goals of palliative systemic chemotherapy are survival benefit and palliation of symptoms[2,3]. Cisplatin has been considered a key substance in combination regimens for metastatic gastroesophageal cancer[4]. Results from a phase 2 study at our institute showed a response rate (RR) of 41% using the combination of cisplatin and gemcitabine, with manageable toxicity[5]. Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant mesothelioma in the EMPHACIS trial[6]. The majority of patients in this study received folic acid and vitamin B12. Vitamin suppletion significantly reduced toxicity of the chemotherapy and did not decrease efficacy parameters. Vitamin suppletion was found to be predictive of increased overall survival in a multivariate regression analysis of prognostic factors derived from this trial[7]. Preclinical evidence demonstrated that differences in the folate environment resulted in a different sensitivity of human cancer cell lines to cisplatin[8,9]. Tumor cells that are relatively cisplatin resistant require lower intracellular folate concentrations for growth[10]. In line, low tumor cell expression levels of the folate receptor (FR), which is a major influx transporter for folates in normal tissues and certain tumors[11], are associated with cisplatin resistance[12,13]. In this paper we first investigated the cisplatin sensitivity of adenocarcinoma cell lines grown under high or low folate conditions. Adenocarcinoma cells grown under high folate conditions were more sensitive to cisplatin and this was associated with higher intracellular platinum accumulation, providing a rationale for supplementation of patients with folates.Based on these in vitro data and the clinical suggestion of increased efficacy in mesothelioma patients we hypothesized that folate supplementation to patients would increase the sensitivity to cisplatin based treatment. We designed a randomized phase 2 trial in order to determine whether supplementation of folic