New directions in the treatment of colorectal cancer: a look to the future

Today, adjuvant 5-fluorouracil based therapy is known to significantly redu ce the relapse rates and the risks of dying from resected colon cancer; che motherapy approximately doubles overall survival of advanced colorectal can cer and second line treatment prolongs the survival of patients compared wi th best supportive care. At the molecular level a number of key genes are o ften mutated in cancer of the colon and some of these key regulators of apo ptosis are discussed (p53 and bcl-2 family of proteins). Dihydropyrimidine dehydrogenase (DPD) activity may be a potential factor controlling fluorour acil (FU) responsiveness at the tumoral level and its importance is stresse d. The rationale of combining FU with DPD inhibitors is fairly strong. Ethy nyluracil, UFT and S1 pursue this strategy while capecitabine has another t he rationale. Drug resistance should be at least partially overcome by comb ination chemotherapy (FU plus mitomycin, oxaliplatin, irinotecan) and combi ned modality (FU+RT) regimens. Improved surgical techniques and radiotherap y have substantially decreased local failure rates for rectal cancers. Fina lly, innovative treatment modalities such as anti-angiogenetic and antimeta static agents, farnesyl transferase inhibitors, vaccine and gene therapy ar e in early clinical trials. (C) 2000 Elsevier Science Ltd. All rights reser ved.