Davis Nancy B, Taber David A, Ansari Rafat H, Ryan Christopher W, George Christopher, Vokes Everett E, Vogelzang Nicholas J, Stadler Walter M
Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2115, Chicago, IL 60637, USA.
J Clin Oncol. 2004 Jan 1;22(1):115-9. doi: 10.1200/JCO.2004.07.165.
Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer.
PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals.
Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively).
Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.
确定蛋白酶体抑制剂PS - 341在IV期肾细胞癌患者中的缓解率、疾病进展时间和毒性。
PS - 341 1.5 mg/m²静脉注射，每周两次，每21天用药2周。在无3至4级毒性反应的情况下，剂量递增至1.7 mg/m²。三个周期后进行重新评估。为评估蛋白酶体抑制情况，患者被随机分配在首次给药前或PS - 341第三个周期后进行肿瘤核心活检。此外，在相同时间间隔采集全血。
入组23例患者；21例可评估缓解情况。2例患者未接受治疗（1例拒绝治疗，1例肿瘤组织不足以进行活检）。18例患者完成至少三个周期的治疗；3例患者在两个周期后出现疾病进展。4级毒性反应为关节痛、腹泻和呕吐。3级毒性反应包括1例出血性血小板减少、贫血、发热性中性粒细胞减少、胃肠道毒性、疼痛、疲劳、神经病变（1例感觉性、1例混合性感觉运动性）和电解质紊乱。7例患者出现1至2级神经病变。发生1例血栓形成和1例胸腔积液。仅观察到1例客观缓解。通过特异性胰凝乳蛋白酶活性（SpA）和胰凝乳蛋白酶/胰蛋白酶活性（ChT:T）测量蛋白酶体活性。给予PS - 341后，全血平均SpA和ChT:T降低（P值分别为0.07和0.11）。
缺乏证据表明PS - 341在转移性肾细胞癌中有临床显著活性。活检和全血样本数量不足，无法得出关于肿瘤内蛋白酶体抑制的结论。不建议在这种疾病背景下进行进一步评估。
