Phase III Randomized Trial Comparing Short-Time Infusion of Oxaliplatin and Capecitabine (XELOX30) with Chronomodulated (XELOX30) in Patients with Advanced and/or Metastatic Colorectal Cancer

Abstract

Chronotherapy attempts to exploit natural biological rhythms such as 24-h time cycles (circadian rhythms) to optimize cancer therapy by decreasing toxicity and improving antitumor efficacy. The clinical relevance of Chronotherapy has been extensively tested in solid tumour patients, with colorectal cancer being the most commonly studied disease type Preclinical studies demonstrate that Chronomodulated treatments may lessen toxicity and improve efficacy in rodent models. In addition, studies in humans show that circadian variation in drug metabolizing enzymes can affect the pharmaco kinetics of agents such as 5-Fu. Chronomodulated xelox is tolerable first line treatment for metastatic and recurrent colorectal cancer.with accepted toxicity profile.better objective response .Several strategies have evolved for exploiting chronobiology cancer chemotherapy. First, assuming that the times of maximal benefit and minimal toxicity are temporally distinct, then the rational selection of the time of drug administration can optimize anti tumour efficacy. Chronomodulated chemotherapy can ameliorate drug related toxicities, and then further escalation to highest maximally tolerated dose (MTD) may improve the therapeutic benefit of drugs with steep dose response curves. This is a phase III prospective study carried out at Ain Shams University Hospital Clinical Ooncology & Nuclear Medicine department in the period between April 2012 and November 2014, where 100 eligible patients who were enrolled in tow arms; 50 patients received conventional xelox and 46 patients received chronomodulated xelox with short term oxaliplatin infusion over 30 minutes. The OS for both groups was analyzed and estimated for 1 year survival in Arm B and Arm A as 100% & 87.5% respectively. Regarding efficacy, the objective response (partial and stable disease) varies among the two studied groups. In Arm A: Among the 50 patients whom entered the study an achieved objective response in 42 patients (84%).In Arm B: The overall objective response (partial response) was achieved in 48 cases representing (96%). although non-significant difference in the one year OS between Arm A and Arm B( 87.5 % versus 100% P value equals 0.056),still noted marginal significance with P value close to significant level. As regard the median OS in one year in the current study shows no significant differences in median overall survival OS between Arm B and Arm A (12 versus 10.5 months) respectively as shown in the Kaplan-Meier curve. These results imply that Chronomodulated chemotherapy with XELOX may have better objective response, better and different toxicity profile favoring the possibility of increase the dose of systemic treatment. Chronomodulated XELOX regimen may reduce overall toxicity and improves efficacy; however, it cannot be excluded that a stricter adherence to the original chronomodulated administration schedule could be the reasonable cause of better toxicity and efficacy. Furthermore, a 30-min infusion of oxaliplatin seems safe and does not increase the severity of chronic neuropathy. In this study the toxicity profile differs markedly among the 2 groups, neuropath and Mucositis were significantly more severe among Xelox group than Chron group. Mucositis was the most annoying side-effect although grade 3 & 4 which unfortunately required interruption of treatment and required systemic treatment with antifungal in addition to the local measures. Vomiting and Neutropenia were significantly more frequent among Xelox group than Chron group.