Fraker D L, Alexander H R, Andrich M, Rosenberg S A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Clin Oncol. 1996 Feb;14(2):479-89. doi: 10.1200/JCO.1996.14.2.479.
To evaluate response rates and systemic and regional toxicity of hyperthermic isolated limb perfusion (ILP) for treatment of in-transit metastases of extremity melanoma using escalating-dose tumor necrosis factor (TNF) in conjunction with melphalan and interferon gamma (IFN).
All patients received IFN 0.2 mg2 for 2 days followed by a 90-minute ILP with TNF and IFN (0.2 mg) given at time 0 and melphalan (10 mg/L limb volume) given at 30 minutes. Twenty-six patients were treated with 4 mg of TNF and 12 patients received 6 mg of TNF. All patients had assessable disease in the perfusion field and all but two patients were assessable for response at 1 month after treatment.
Mean peak perfusate TNF levels in the 4-mg group were 4.8 micrograms/mL, compared with 7.4 micrograms/mL for the 6-mg group (P = .03). The complete response rate in the 4-mg TNF group was 76%, with an overall objective response rate of 92%, compared with 36% and 100% for the 6-mg group. Subgroup analyses showed that the lower complete response rate in the 6-mg TNF group was not explained by differences in disease burden or prior regional therapy. Systemic drug toxicity was short-lived, easily managed, and related to perfusate leak more than to TNF perfusate dose. Regional toxicity, particularly painful myopathy and neuropathy, was greater with the 6-mg dose level and was considered dose-limiting.
ILP with 4 mg TNF, IFN, and melphalan can lead to complete local responses in the majority of patients with extremity melanoma. Escalating the TNF dose to 6 mg did not increase the complete response rate and increased regional toxicity.
评估使用递增剂量肿瘤坏死因子（TNF）联合美法仑和干扰素γ（IFN）进行热灌注肢体隔离术（ILP）治疗肢体黑色素瘤皮下转移的缓解率、全身及局部毒性。
所有患者接受2天0.2mg²的IFN治疗，随后进行90分钟的ILP，于时间0给予TNF和IFN（0.2mg），30分钟时给予美法仑（10mg/L肢体体积）。26例患者接受4mg的TNF治疗，12例患者接受6mg的TNF治疗。所有患者在灌注区域均有可评估的疾病，除2例患者外，所有患者在治疗后1个月均可评估缓解情况。
4mg组灌注液中TNF的平均峰值水平为4.8μg/mL，而6mg组为7.4μg/mL（P = 0.03）。4mg TNF组的完全缓解率为76%，总体客观缓解率为92%，而6mg组分别为36%和100%。亚组分析显示，6mg TNF组较低的完全缓解率不能用疾病负担或既往局部治疗的差异来解释。全身药物毒性短暂，易于处理，且与灌注液渗漏的关系大于与TNF灌注液剂量的关系。6mg剂量水平的局部毒性，尤其是疼痛性肌病和神经病变更严重，被认为是剂量限制性毒性。
使用4mg TNF、IFN和美法仑进行ILP可使大多数肢体黑色素瘤患者获得完全局部缓解。将TNF剂量增至6mg并未提高完全缓解率，反而增加了局部毒性。
