Daniel G. Haller, MD

During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise in fighting colorectal cancer.

Advances in the treatment ofmetastatic colorectal cancer inthe past several years havebeen expeditious and exciting-evenchaotic-but with the median survivaldoubled since the use of single-agentfluoropyrimidines alone. However, newquestions continue to arise, directly affectingour daily practice in the care ofpatients with colorectal cancer. One ofthese issues, the optimal therapy formetastatic colorectal cancer, is wonderfullyexplored by Dr. Saltz in thisissue of ONCOLOGY. To understandthis issue better, we may have to approachthe question a little differently:That is, is it possible to standardizetreatment options for metastatic colorectalcancer?

From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.

It is a continuing challenge for oncologists to effectively treatadvanced/metastatic pancreatic and biliary cancer. Both irinotecan(CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activityagainst these diseases with different mechanisms. Preclinical andclinical data also suggest additive or synergistic effects of the combinationof these two agents with few or no overlapping toxicities. Phosphorylationof gemcitabine, a process of intracellular activation of theagent, is dose-rate dependent. It has been suggested that the fixed-doserateinfusion of gemcitabine increases the concentration of intracellulartriphosphate gemcitabine, which in turn may result in more objectiveresponses and longer median survival compared to the standard infusion.This phase I study tests the toxicity of the combination of irinotecanwith fixed-dose-rate infusion of gemcitabine, and determines thedose of the combination for phase II investigation.

The role of sentinel lymph node identification has been investigated over the past decade in a variety of malignancies. It has become part of standard care for melanoma. Its role in breast cancer is evolving, but with the completion of two large randomized clinical trials, it will probably be added to the surgical armamentarium for the management of most breast cancers. Studies have been proposed or are under way to evaluate sentinel node mapping in head and neck cancer, penile and vulvar cancer, and gastrointestinal cancers.

The article by Drs. Khayat and Gil-Delgado outlines the exciting new developments in the treatment of advanced colorectal cancer with irinotecan (CPT-11 [Camptosar]) and oxaliplatin. Although the development of these drugs provides an alternative to fluorouracil (5-FU) in the treatment of this common tumor, it is still unclear how to optimally integrate these promising compounds into therapy for colorectal cancer.

Efforts to improve the length and quality of life, as well as to expand treatment options, for patients with metastatic colorectal cancer have only recently become more successful. With

UFT and leucovorin (Orzel) is a combination of tegafur and uracil in a molar ratio of 1:4. Tegafur, a prodrug of 5-fluorouracil (5-FU), is converted to 5-FU by the hepatic cytochrome P450 pathway, whereas uracil enhances the

The new platinum compound oxaliplatin (Eloxatin) appears tohave activity, either alone or in combination, as both first- and second-line

Postoperative combined-modality therapy with fluorouracil (5-FU) and radiation therapy is accepted practice for high-risk rectal cancer. Postoperative pelvic radiotherapy alone may improve pelvic control, but is not associated with an improvement in survival.

The combination of irinotecan and fluorouracil (5-FU) is synergistic when applied to human colon cancer cell lines in vitro and appears to be schedule-dependent: maximal activity occurs when irinotecan is administered prior to 5-FU. In this phase I study, irinotecan is administered in combination with UFT and leucovorin in patients with advanced solid tumors.