Yahanda A M, Alder K M, Fisher G A, Brophy N A, Halsey J, Hardy R I, Gosland M P, Lum B L, Sikic B I
Department of Medicine, Stanford University School of Medicine, Palo Alto, CA.
J Clin Oncol. 1992 Oct;10(10):1624-34. doi: 10.1200/JCO.1992.10.10.1624.
To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer.
Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI.
Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression.
Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).
确定癌症患者中，环孢素（CsA）与依托泊苷联合使用3天时的最大耐受剂量（MTD）。
72名登记患者中，26名最初接受CsA和依托泊苷治疗。46名患者先单独接受依托泊苷治疗，直至疾病进展，其中31名随后接受CsA和依托泊苷治疗。CsA以2小时负荷剂量（LD）和3天持续输注（CI）方式给药；剂量从2 mg/kg LD和5 mg/kg/d CI逐步递增至8 mg/kg LD和24 mg/kg/d CI。
57名患者接受了113个周期的CsA与依托泊苷联合治疗。当CsA剂量≥5 mg/kg LD且≥15 mg/kg/d CI时，91%的周期中稳态血清CsA水平（非特异性免疫测定）超过2000 ng/mL。CsA的主要剂量相关毒性是可逆性高胆红素血症，在CsA水平>2000 ng/mL的疗程中，78%出现该症状。CsA与依托泊苷联用时，骨髓抑制和恶心更严重。CsA的其他毒性包括低镁血症（60%）、高血压（29%）和头痛（21%）。12%的周期中肾毒性为轻度，2%为重度。4名患者加用CsA后肿瘤出现消退（1例非霍奇金淋巴瘤、1例霍奇金病和2例卵巢癌）。对4名有反应患者中的3名进行了肿瘤活检，结果mdr1表达呈阳性。
与依托泊苷联合使用时，短期给药期间血清CsA水平可达4 μmol/L（4800 ng/mL），且毒性可接受。推荐的成人CsA剂量为负荷剂量5至6 mg/kg，随后持续输注15至18 mg/kg/d，共60小时。应监测CsA血药浓度并调整剂量，使CsA水平达到2.5至4 μmol/L（3000至4800 ng/mL）。可逆性高胆红素血症可能是CsA抑制P-糖蛋白功能的有用标志物。与高剂量CsA联用时，依托泊苷剂量应降低约50%，以补偿CsA对依托泊苷的药代动力学影响（Lum等人，《临床肿瘤学杂志》，10:1635 - 1642，1992年）。
