Potential of Xeloda in colorectal cancer and other solid tumors.
For over four decades, 5-fluorouracil (5-FU) has been the mainstay of therapy for colorectal cancer and a major cytotoxic agent for treating gastrointestinal tumors and a variety of others, including breast and head and neck cancers. Xeloda (capecitabine) is a new drug that is administered orally and has been rationally designed to generate 5-FU selectively within solid tumors. Theoretically, it has two major advantages, which should translate into an improved therapeutic index: firstly, enhanced drug concentration at the cancer site and therefore greater anti-tumor activity and secondly, reduced drug levels in non-tumor tissues, with a consequent reduction in systemic toxicity. After promising preclinical studies, phase I clinical trials of Xeloda have been performed with a variety of schedules, both with and without the oral biomodulator leucovorin. Anti-tumor activity has been observed with all regimens tested. In the setting of colorectal cancer, a randomized phase II study substantiated the phase I reports of activity and established the most promising regimen for phase III clinical trials. Patients in the phase II trial were randomly selected to receive either continuous Xeloda, intermittent Xeloda or intermittent Xeloda plus leucovorin. There were complete or partial responses in 21% of patients in the continuous arm, 24% in the intermittent arm, and 23% in the arm with intermittent Xeloda plus leucovorin. In addition, 51-63% of patients in each arm achieved stable disease. Therapy was well tolerated in all three arms. The intermittent regimen of Xeloda alone was associated with a longer time to disease progression and offered a one-week rest period to the patient. It was therefore selected for subsequent studies. Two randomized phase III trials of Xeloda versus the 'Mayo' regimen in patients with advanced colorectal cancer have completed recruitment. They are designed to demonstrate at least equivalent efficacy, with important secondary endpoints of comparisons of toxicity, medical care utilization, and quality of life. No formal results are yet available from these studies. The same regimen of Xeloda is now being evaluated in a large scale adjuvant study, which is expected to recruit approximately 1,700 Dukes' C colonic cancer patients (X-ACT study). The modest toxicity of Xeloda (particularly its low incidence of neutropenia) makes it a suitable candidate for novel combination therapies involving other agents that are active in colorectal cancer, including camptothecin and its analogues, oxaliplatin and radiotherapy. Further studies of Xeloda can be expected with other diseases known to be responsive to fluoropyrimidines, together with diseases traditionally thought to be resistant.
Cassidy
J
J
University of Aberdeen, Aberdeen, Scotland, UK. j.cassidy@abdn.ac.uk
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069287:Capecitabine; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil