Yang J C, Rosenberg S A
Surgery Branch, National Cancer Institute, Bethesda, Maryland, USA.
Cancer J Sci Am. 1997 Dec;3 Suppl 1:S79-84.
This article compares the pharmacokinetics, toxicity, and clinical efficacy of high-dose intravenous, low-dose intravenous, and intermediate-dose subcutaneous recombinant interleukin-2 (rIL-2) regimens in patients with measurable metastatic renal cell carcinoma.
This trial began as a two-arm randomized study comparing two bolus intravenous rIL-2 regimens. High-dose (720,000 IU/kg) and low-dose (72,000 IU/kg) rIL-2 were administered every 8 hours for up to 15 consecutive doses. Later, a third arm of outpatient subcutaneous rIL-2 (week 1: 250,000 IU/kg/day for 5 of 7 days; weeks 2-6: 125,000 IU/kg/day for 5 of 7 days) was added, and only concurrently randomized patients were compared. A sample of patients underwent pharmacokinetic studies of serum IL-2 levels following their first dose. Accrual to this study is ongoing and results are preliminary.
In the two-arm comparison of high-dose versus low-dose intravenous rIL-2, 116 and 112 patients have been randomized, respectively, and the median follow-up is 52 months. Low-dose rIL-2 induced significantly less hypotension, thrombocytopenia, malaise, pulmonary toxicity, and neurotoxicity than high-dose rIL-2. The initial overall response rate (partial plus complete responses) was 19% with high-dose rIL-2 and 10% with low-dose rIL-2. Responses to high-dose rIL-2 tended to be more durable. With 54 to 56 patients randomized per arm in the three-arm comparison, the high-dose intravenous, low-dose intravenous, and subcutaneous outpatient rIL-2 regimens have produced response rates of 16%, 4%, and 11%, respectively. Subcutaneous rIL-2 therapy was infrequently associated with grade 3 or 4 toxicity (similar to low-dose intravenous rIL-2 therapy). Survival data remain incomplete with median follow-up in the three-arm trial at 27 months.
The optimal IL-2 regimen for treating metastatic renal cell carcinoma is not known. Alternative regimens with much less acute toxicity than high-dose IL-2 can cause regression of renal cell carcinoma, but duration of therapy, chronicity of symptoms, and quality-of-life issues may be important in properly evaluating the tolerability of different regimens. Because the main benefit of IL-2 therapy is not its initial response rate but its induction of durable, complete responses, further accrual and follow-up will be necessary to compare properly the impact of these regimens on patient survival.
本文比较高剂量静脉注射、低剂量静脉注射和中等剂量皮下注射重组白细胞介素-2（rIL-2）方案在可测量转移性肾细胞癌患者中的药代动力学、毒性和临床疗效。
本试验最初是一项双臂随机研究，比较两种大剂量静脉注射rIL-2方案。高剂量（720,000 IU/kg）和低剂量（72,000 IU/kg）rIL-2每8小时给药一次，连续给药最多15剂。后来，增加了第三组门诊皮下注射rIL-2（第1周：250,000 IU/kg/天，7天中的5天；第2 - 6周：125,000 IU/kg/天，7天中的5天），仅对同时随机分组的患者进行比较。一部分患者在首次给药后进行了血清IL-2水平的药代动力学研究。本研究仍在进行入组，结果为初步结果。
在高剂量与低剂量静脉注射rIL-2的双臂比较中，分别有116例和112例患者被随机分组，中位随访时间为52个月。低剂量rIL-2引起的低血压、血小板减少、不适、肺部毒性和神经毒性明显低于高剂量rIL-2。高剂量rIL-2的初始总体缓解率（部分缓解加完全缓解）为19%，低剂量rIL-2为10%。高剂量rIL-2的缓解往往更持久。在三臂比较中，每组随机分组54至56例患者，高剂量静脉注射、低剂量静脉注射和皮下门诊rIL-2方案的缓解率分别为16%、4%和11%。皮下注射rIL-2治疗很少与3级或4级毒性相关（与低剂量静脉注射rIL-2治疗相似）。三臂试验的中位随访时间为27个月，生存数据仍不完整。
治疗转移性肾细胞癌的最佳IL-2方案尚不清楚。与高剂量IL-2相比，急性毒性小得多的替代方案可使肾细胞癌消退，但治疗持续时间、症状的慢性程度和生活质量问题在正确评估不同方案的耐受性方面可能很重要。由于IL-2治疗的主要益处不是其初始缓解率，而是其诱导持久完全缓解的能力，因此需要进一步入组和随访，以正确比较这些方案对患者生存的影响。
