Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma.
Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma.
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DOI：
10.1038/bjc.1998.214
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发表时间：
1998-04
影响因子：
8.8
通讯作者：
Gore, M E
中科院分区：
文献类型：
--
作者：
Johnston, S R;Constenla, D O;Moore, J;Atkinson, H;A'Hern, R P;Dadian, G;Riches, P G;Gore, M E
本研究的目的是在一项随机II期试验中评价联合生物化疗与单纯化疗在转移性黑色素瘤患者中的疗效和毒性。65例转移性黑素瘤患者（ECOG体力状态0或1）随机接受静脉注射BCNU 100 mg m（-2）（第1天，交替疗程），顺铂25 mg m（-2）（第1-3天），DTIC 220 mg m（-2）（第1-3天）和口服他莫昔芬40 mg（BCDT方案），联合（n = 35）或不联合（n = 30）皮下白细胞介素2（IL-2）18 x 10（6）iu t.d.s. (day- 2），9 x 10（6）iu b.d. (day- 1和0）和干扰素2 α（IFN-α）9 MU（第1-3天）。免疫激活的证据通过外周血淋巴细胞的流式细胞术分析来确定。治疗每4周重复一次，最多6个疗程，取决于反应。BCDT联合IL-2/IFN-α治疗的总缓解率为23% [95%置信区间（CI）10-40%]，其中1例完全缓解（CR）和7例部分缓解（PR），单独BCDT治疗的总缓解率为27%（95% CI 12-46%），其中8例PR;缓解的中位持续时间分别为2.8个月和2.5个月。两组的反应部位相似。两组的无进展生存期或总生存期无差异（BCDT联合IL-2/IFN α的中位生存期为5个月，BCDT单独治疗的中位生存期为5.5个月）。尽管皮下IL-2 3天导致显著的淋巴细胞减少，但CD 56-（NK细胞）和CD 3/HLA-DR阳性（活化T细胞）亚群的百分比显著升高表明免疫活化的证据，而CD 4或CD 4 T细胞亚群的百分比没有任何变化。毒性评估显示，联合化疗组严重血小板减少的发生率显著高于单用化疗组（37% vs 13%，P = 0.03），3/4级流感样症状（20% vs 10%）和疲乏（26% vs 13%）的发生率也较高。在一项随机II期试验中，在BCDT化疗中添加皮下IL-2和IFNalpha会导致免疫激活，但并未提高转移性黑色素瘤患者的缓解率，而且确实可能会增加一些治疗相关的毒性。
The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to BCDT chemotherapy in a randomized phase II trial resulted in immune activation but did not improve response rates in patients with metastatic melanoma, and indeed may increase some treatment-related toxicity.