Palmeri S, Meli M, Danova M, Bernardo G, Leonardi V, Dastoli G, Rausa L, Russo A, Filippelli G, Palmieri G, Russo A, Della Vittoria Scarpati M, Lo Russo V, Di Lauro L, Colucci G, Bruni G, Piazzi M, Gebbia N, Spada S
Institute of Clinical Medicine I, University of Palermo, Italy.
J Cancer Res Clin Oncol. 1998;124(3-4):191-8. doi: 10.1007/s004320050154.
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.
生化调节是癌症化疗中最有趣的领域之一。α干扰素（IFNα）是一种细胞因子，能够通过多种机制影响5-氟尿嘧啶（5FU）的药效学。为了证实文献中出现的一些数据，我们启动了一项多中心随机研究，比较5FU与IFNα-2a联合用药与单独使用5FU治疗晚期或转移性结肠癌的效果。205例结肠癌患者（5FU组104例，5FU + IFNα-2a组101例）纳入最终意向性分析。直肠癌患者不被视为符合条件。所有患者均有可测量的病灶，年龄在75岁及以下，卡诺夫斯基指数至少为60，骨髓、肾脏、肝脏和心脏功能良好。既往未接受过化学免疫治疗。治疗方案为第1至5天静脉输注750mg/m² 5FU（4小时），然后从第12天开始每周静脉推注一次，联合或不联合皮下注射IFNα-2a，每周三次（起始剂量3×10⁶IU，如耐受则增至9×10⁶IU）。患者接受治疗直至病情进展，或如有效则最多治疗48周，然后观察2年。该研究的主要终点是客观临床缓解（OR）；次要参数是疾病进展时间、总生存期和进展后死亡时间。临床缓解和毒性测量均采用WHO标准。如果因5FU、IFNα-2a或两者导致明显毒性，则预先计划减少剂量。通过单因素和多因素分析研究主要和次要终点与治疗之间的关联。共有47例患者实现了有记录的缓解。联合用药组的OR为25%，而5FU组为21%；这种差异无统计学意义（P = 0.6）。肿瘤负荷较小（低于5cm²）的患者在两组中缓解的可能性更高。试验组患者的累积无进展概率更高，但无统计学意义。总体中位生存期为47.1周，而对照组和试验组分别为43.7周和48.5周。联合用药明显比单独使用5FU毒性更大，试验组最常见的副作用是白细胞减少，对照组是恶心和呕吐。总之，这些结果相当令人失望，5FU + IFNα-2a不能被视为晚期结肠癌的标准治疗方法。
