title: 5-Fluorouracil plus interferon alpha-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: a multicentric randomized study.
abstract: Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.
authors.affiliation: Institute of Clinical Medicine I, University of Palermo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Palmeri
authors.forename: M
authors.initials: M
authors.lastname: Meli
authors.forename: M
authors.initials: M
authors.lastname: Danova
authors.forename: G
authors.initials: G
authors.lastname: Bernardo
authors.forename: V
authors.initials: V
authors.lastname: Leonardi
authors.forename: G
authors.initials: G
authors.lastname: Dastoli
authors.forename: L
authors.initials: L
authors.lastname: Rausa
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.forename: G
authors.initials: G
authors.lastname: Filippelli
authors.forename: G
authors.initials: G
authors.lastname: Palmieri
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.forename: M
authors.initials: M
authors.lastname: Della Vittoria Scarpati
authors.forename: V
authors.initials: V
authors.lastname: Lo Russo
authors.forename: L
authors.initials: L
authors.lastname: Di Lauro
authors.forename: G
authors.initials: G
authors.lastname: Colucci
authors.forename: G
authors.initials: G
authors.lastname: Bruni
authors.forename: M
authors.initials: M
authors.lastname: Piazzi
authors.forename: N
authors.initials: N
authors.lastname: Gebbia
authors.forename: S
authors.initials: S
authors.lastname: Spada
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D005472:Fluorouracil