A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma

Colorectal carcinoma is the second leading cause of cancer death in the Western countries and almost 50% of these patients die because of problems related to disease progression. Although a higher rate of response has been achieved with the newest polychemotherapy regimens, patients with metastatic colorectal cancer still have poor prognosis with a dismal 5-year survival rate (Gill et al, 2003). 5-Fluorouracil (5-FU) alone or in combination with biomodulators, such as folinic acid (FA), levamisol, interferon alpha, has long been the only systemic treatment in adjuvant setting and advanced stage of disease (Francini et al, 1994; Grem, 1996; O’Connell, 1998; Von Hoff, 1998; Skibber, 2001), but new drugs such as CPT-11 and the novel platinum derivative oxaliplatin have recently been successfully combined with 5-FU in different administration schedules and dosages (Skibber, 2001; Von Hoff, 1998). The combination of oxaliplatin with FA and infusional 5-FU (FUFA) is currently being investigated by the American Food and Drug Administration (FDA) in the first-line treatment for advanced colorectal carcinoma. This new generation of drugs has been evaluated in a number of clinical trials and has certainly improved clinical response rates and survival; unfortunately, the average overall survival still remain within the 20 months also in the most optimistic studies (Grothey and Schmoll, 2001; Kohne, 2003; Goldberg et al, 2004; Tournigand et al, 2004). The results of these trials, therefore, justify the continuing search for new drugs or more active drug combinations. It has been shown that the difluorinated analogue of deoxycytidine known as gemcitabine (GEM) (difluoro-2′,2′-deoxycytidine) synergistically interacts with 5-FU in terms of antitumour activity in colon carcinoma cells in vitro (Correale et al, 1999). The combination of these two drugs administered by using different schedules and dosages has also showed a significant antitumour activity in patients with a different gastroenteric malignancies (Berlin et al, 1998–1999; Schulz et al, 1998; Correale et al, 1999; Hidalgo et al, 1999) including colo-rectal carcinoma (Madajewicz et al, 2000). Previous studies of our group have in addition shown a supra-additive cytotoxic activity and apoptosis-inducing capacity of GEM combined with oxaliplatin and FUFA (GOLF) in colon cancer cell lines in vitro (Correale et al, 2002 and unpublished results). On these bases, we have designed a phase I–II clinical trial aimed to investigate in patients with advanced colorectal carcinoma who had received at least a line of chemotherapy, the toxicity and the antitumour activity of a new polychemotherapy regimen composed by GEM plus oxaliplatin and FUFA administered using the schedule suggested by de Gramont et al (1997), (1998)) (FOLFOX-4).