Evaluation of factors influencing 5-fluorouracil-induced diarrhea in colorectal cancer patients. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) study.

Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with colorectal cancer and can result in severe morbidity and mortality. No well-defined prognostic factors influencing 5FU-associated diarrhea have been identified, which means its occurrence is unforeseeable. The aim of this study was to check whether any characteristics related to patients or chemotherapy could allow the identification of subsets of patients at higher risk of developing diarrhea while receiving a regimen containing 5FU. A logistic regression analysis was performed with age, sex, site of primary tumor, presence of primary tumor, presence of colostomy, time since surgery, number of courses of chemotherapy, diarrhea in previous courses, season of treatment, and chemotherapeutic regimens used as model parameters to predict occurrence of diarrhea in 258 colorectal cancer patients receiving a 5FU-containing regimen. Presence of primary tumor (P = 0.004), previous episodes of chemotherapy-related diarrhea (P = 0.00005) and summer season (P = 0.014) were found to be significant risk factors for developing diarrhea. The other variables examined, such as age, sex, chemotherapeutic regimen, site of primary tumor, presence of colostomy, and time since surgery, were not significantly correlated to diarrhea. Chemotherapeutic regimen was the only parameter that allowed prediction of the severity of diarrhea: 5FU/6S-leucovorin/interferon caused more severe diarrhea, followed by 5FU/leucovorin weekly. Although the analysis of these clinical features does not seem to allow the definition of a well-defined subset of colorectal cancer patients at higher risk of 5FU-induced diarrhea, it can be recommended that patients with primary tumor, or who have experienced diarrhea in earlier courses of chemotherapy or are receiving treatment in summer should be carefully monitored, especially in the first cycles.

Treatment of colorectal cancer. Current guidelines and future prospects for drug therapy.

Colorectal carcinoma is one of the most common cancers in Western countries (yearly incidence rate of 1:3000), and represents, after lung cancer, the second leading cause of deaths due to cancer. During the past decades, knowledge about this carcinoma has considerably increased, but little progress has been made in improvement in patient survival. At least 40% of patients with colorectal cancer will have metastases sometime during the course of their illness. In colon cancer, the first therapeutic approach is surgery, but the important role of adjuvant chemotherapy in these patients, in terms of disease-free survival and overall survival benefit, is now well established. Until today, standard therapy was represented by fluorouracil plus levamisole and/or calcium folinate (folinic acid). Other strategies are represented by monoclonal antibodies (mAb), which improve survival, (with a decrease in mortality by 32%), and by portal vein fluorouracil, alone or in combination with systemic therapy. In rectal cancer, the best results have been obtained with a combination of radiotherapy and chemotherapy. In advanced colorectal cancer, a standard treatment has not yet been established. This disease is usually considered as poorly chemosensitive and for more than 30 years fluorouracil has been the standard drug. Tumour response rates (partial+complete) for patients treated with bolus intravenous fluorouracil are 10 to 15%, with a median survival about 1 year. Many attempts have been made to improve these results. Biochemical modulation of fluorouracil is one of the most interesting strategies developed in the last few years in an attempt to increase the therapeutic index of this compound. Another way has been to administer fluorouracil by continuous infusion. Further innovative compounds such as irinotecan and raltitrexed are now being evaluated in clinical trials. Preliminary data from phase II and III studies have provided encouraging results on the use of these new drugs. In metastatic disease confined to the liver, the possibility of locoregional therapy through implantable pumps should be taken into consideration.

[Locoregional chemotherapy of liver metastasis from colorectal carcinoma]. / Chemioterapia locoregionale delle metastasi epatiche da carcinoma del colon-retto.

Hepatic metastases are a major cause of death in patients with colorectal carcinoma. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients and surgical resection is feasible in approximately 20% of patients. Infusion of cytotoxic agents into the hepatic artery is the most promising form of therapy for unresectable hepatic metastases. The recent development of a totally implantable pump has allowed prolonged infusion of chemotherapeutic agents with a good compliance and quality of life of the patients. The rationale for hepatic arterial infusion (HAI) present an anatomical and pharmacological basis with the use of agents with high hepatic extraction resulting in minimal systemic toxicity. The results of eight randomized trial assessing the value of HAI Floxuridine shows that such regional chemotherapy increases the likelihood of hepatic response compared with systemic treatment (52% vs 15%). Survival information is difficult to evaluate because some of the studies are small, some had a crossover design and some others had bias factors. Extrahepatic disease develops in 40-70% of patients undergoing HAI; the use of systemic therapy plus HAI may produce a decrease in extrahepatic disease. Further studies of combined systemic/arterial regiment are necessary.