Rosso R, Sertoli M R, Queirolo P, Sanguineti O, Barzacchi M C, Mariani G L, Miglio L, Venturini M, Toma S
Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Ann Oncol. 1992 Jul;3(7):559-63. doi: 10.1093/oxfordjournals.annonc.a058261.
The aim of this phase I study was to exploit the potential efficacy of an alpha-2a-interferon (alpha-2a-IFN)-subcutaneous interleukin-2 (IL-2) combination, bypassing the toxicity usually associated with bolus or continuous infusion of IL-2. Therefore, nineteen patients with metastatic malignancies (7 melanomas, 6 renal cell carcinomas and 6 soft tissue sarcomas) were treated according to a dose escalating schedule of subcutaneous IL-2 combined with intramuscular alpha-2a-IFN for 5 days/week for 3 consecutive weeks. Cycles were repeated every 2-4 weeks unless disease progressed. Alpha-2a-IFN (3 MU/die) was given continuously, including during the rest weeks. IL-2 doses were started at 2 MIU/day/sqm and the MTD of 6 MIU/day/sqm was progressively reached. The dose of IL-2 was given twice daily every 12 hours. Both of the cytokines were administered in an outpatient setting. The main side effects were fever, chills, fatigue, hypotension, nausea and vomiting. Toxicity was correlated with IL-2 dose level. It was found to be mild at 2 and 4 MIU/day/sqm, while, in contrast, grade III toxicity was observed only at the highest dose of 6 MIU/day/sqm. However, this grade III toxicity was manageable and did not prevent continuation of the treatment as long as the dose was not increased above 6 MIU/day/sqm. Three patients, one with melanoma and two with renal cell carcinomas, obtained clinical partial responses. In eight patients, stable disease, and in the remaining eight, progression, were observed. The data suggest that the combined use of the two BRMs has manageable side effects and would seem to be efficacious. A phase II study at the recommended dose of 6 MIU/day is now necessary.
本I期研究的目的是利用α-2a干扰素（α-2a-IFN）与皮下注射白细胞介素-2（IL-2）联合使用的潜在疗效，避免通常与大剂量推注或持续输注IL-2相关的毒性。因此，19例转移性恶性肿瘤患者（7例黑色素瘤、6例肾细胞癌和6例软组织肉瘤）按照皮下IL-2联合肌肉注射α-2a-IFN的剂量递增方案进行治疗，每周5天，连续3周。除非疾病进展，每2-4周重复一个周期。α-2a-IFN（3 MU/天）持续给药，包括在休息周。IL-2剂量从2 MIU/天/平方米开始，逐步达到6 MIU/天/平方米的最大耐受剂量（MTD）。IL-2剂量每12小时每日给药两次。两种细胞因子均在门诊给药。主要副作用为发热、寒战、疲劳、低血压、恶心和呕吐。毒性与IL-2剂量水平相关。在2和4 MIU/天/平方米时毒性较轻，相反，仅在最高剂量6 MIU/天/平方米时观察到III级毒性。然而，这种III级毒性是可控的，只要剂量不增加到6 MIU/天/平方米以上，就不会妨碍继续治疗。3例患者，1例黑色素瘤和2例肾细胞癌患者获得了临床部分缓解。8例患者病情稳定，其余8例患者病情进展。数据表明，两种生物反应调节剂联合使用副作用可控，似乎有效。现在有必要进行一项II期研究，推荐剂量为6 MIU/天。
