A randomized phase II trial of 5-fluorouracil, with or without human interferon-β, for advanced colorectal cancer

Abstract

Colorectal cancer has an annual incidence of 53 cases per 100 000 in the USA and Europe, representing 15% of all malignant tumors (Beard et al, 1995; Netherlands Cancer Registry, 1989). Approximately 30% of patients present with advanced disease, and about 60% of these cases are no longer amenable to surgery. The prognosis for these patients is poor.The fluorinated pyrimidine 5-fluorouracil (5-FU) has been the principal treatment for advanced colorectal cancer for the past 4 decades (Heidelberger et al, 1957). Therapy with 5-FU leads to objective response in only 8-20% of patients, with few complete responses and minimal improvement in survival (Carter, 1976;Leichman et al, 1995;Moertel, 1982). Dosage of 5-FU is limited by the occurrence of mucosal and neutropenic toxicities (Moertel, 1975).Various modulating agents have been used in an attempt to synergistically enhance 5-FU's cytotoxicity. Results have so far been disappointing. Improved response rates have been reported with the combination of 5-FU and leucovorin, but responses were mainly partial rather than complete and most were of short duration. Two randomized studies observed significantly increased survival time for 5-FU with leucovorin (Ehrlichman et al, 1988;Poon et al, 1989), but a meta-analysis and two other randomized studies failed to confirm improvement over 5-FU monotherapy (Piedbois et al, 1992;Leichman et al, 1995;O'Dwyer et al, 1996). Early clinical trials reported encouraging results with the combination of 5-FU and interferon alpha (IFN-α), including tumor response rates as high as 35-63% and median survival times of up to 18 months. However, the cost was a high level of toxicity: in particular, fever, constitutional symptoms and myelosuppression (Wadler et al, 1989;Kemeny et al, 1990;Pazdur et al, 1990). Unfortunately, no improvements in response rate or survival time have been observed in further randomized trials of 5-FU with IFN-α versus 5-FU monotherapy (Hill et al, 1995;Greco et al, 1996) or 5-FU with leucovorin (Corfu-A Study Group, 1995).The interferons are a well-recognized group of naturally occurring proteins with antiviral, immunomodulatory and antiproliferative properties. Based on antigenic specificity, physico-chemical properties and cellular origin, they are classified as type I or type II. The type I interferons, IFN-α and IFN-β, are produced by leucocytes and fibroblasts respectively. IFN-β has a 30% level of amino acid homology with IFN-α (Taniguchi et al, 1980), and binds to the type I interferon receptor with higher affinity than IFN-α (Ruzicka et al, 1987). There is evidence for a receptorassociated protein specifically involved with IFN-β's signalling pathway and not IFN-α's (Platanias et al, 1994). Although the mechanisms of the interferons' anti-tumor activity and 5-FU modulation remain poorly understood, preclinical data suggest a theoretical benefit for IFN-β over IFN-α in the treatment of colorectal cancer. Antiproliferative activity against some tumor cell lines in vitro appears greater for IFN-β than IFN-α (Bo...

Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines

“…[1][2][3] As another strategy, other clinical trials have examined administration of recombinant cytokines such as interferons (IFNs) or interleukin 2 (IL-2) in combination with 5-FU in advanced colorectal cancer. [4][5][6][7][8] Several studies have demonstrated that catabolizing and anabolizing enzymes for 5-FU influence the sensitivity of cancer cells against this agent. 9 Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolic pathway of 5-FU.…”

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

“…In the adjuvant setting, a trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP-C05) also failed to show any advantage for 5FU + LV + α-IFN over 5FU + LV in patients with stage II-III colon cancer (Wolmark et al, 1998). On-going studies are currently addressing the interest of other types of interferon, such as α-2c IFN and β-IFN (Villar Grimalt et al, 1999). However, new agents, such as CPT-11 (irinotecan) (Douillard et al, 2000;Saltz et al, 2000) or oxaliplatin (de Gramont et al, 2000) have demonstrated clinical benefits in advanced colorectal cancer, and are therefore more plausible candidates for the adjuvant setting.…”

Interferon-b Inhibits Liver Metastases from Murine Colon 26 Carcinoma and its Highly Metastatic Variant

“…In addition, the combination of IFN-β and 5-fl uorouracil (5-FU) demonstrated an increased in vivo antitumor effect in comparison to 5-FU monotherapy. 16 In this study, the inhibitory effects of IFN-β were examined in a model of liver metastases from CT 26 and its highly metastatic variant.…”