Sparano J A, Wiernik P H, Hu X, Sarta C, Henry D H, Ratech H
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
Med Oncol. 1998 Apr;15(1):50-7. doi: 10.1007/BF02787345.
Protease inhibitors are an important new class of agents for the treatment of human immunodeficiency virus (HIV) infection. The purpose of our trial was to determine the feasibility of combining the protease inhibitor saquinavir with a 96-hour continuous intravenous infusion of cyclophosphamide (800 mg/M2), doxorubicin (50 mg/M2, and etoposide (240 mg/M2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma associated with HIV infection. The effect of saquinavir on CDE-induced myelosuppression, CD4 lymphopenia, and non-hematologic toxicity was also sought. Twelve patients with HIV-related lymphoma received CDE every 28 or more days. All patients received saquinavir (600mg PO TID), filgrastim and Pneumocystis carinii and fungal prophylaxis. Patients also received either stavudine (n = 2) or both stavudine and didanosine (n = 10). Toxicity was analyzed using the NCI Common Toxicity Criteria for each cycle and the data were compared with the data from our prior study of CDE plus didanosine. An interim analysis was performed after accrual of the first 12 patients in order to assess toxicity. Severe (grade 3 or 4) mucositis occurred in eight of 12 patients (67%) treated with CDE plus saquinavir compared with three of 25 patients (12%) in our prior study treated with CDE without saquinavir (P < 0.001). In logistic regression analysis, saquinavir use was the only factor associated with a significantly greater risk of severe mucositis (relative risk 7.9; P = 0.03). Saquinavir use was not associated with a significant difference in the incidence of febrile neutropenia, prolonged neutropenia, chemotherapy dose reduction, or in the degree of myelosuppression. The decrease in CD4 lymphocytes for patients treated with saquinavir (absolute decrease of 23/microL, or a 26% decrease from baseline) was significantly less than for patients treated without saquinavir in the prior study (absolute decrease of 91/microL, or 42% decrease from baseline; P = 0.05). Four of 10 patients (40%) treated with saquinavir had an increase in CD4 lymphocytes of > or = 10/microL compared with none of 25 patients (0%) treated without saquinavir (P < 0.001). Combination of the protease inhibitor saquinavir with infusional CDE in patients with HIV-associated lymphoma was associated with a significant increase in the incidence of severe mucositis. This finding suggests that saquinavir may alter the metabolism of one of more of the cytotoxic agents in the CDE regimen, and underscores the need for careful investigation regarding the use of the protease inhibitors in patients receiving chemotherapy.
蛋白酶抑制剂是治疗人类免疫缺陷病毒（HIV）感染的一类重要新型药物。我们试验的目的是确定将蛋白酶抑制剂沙奎那韦与环磷酰胺（800mg/M²）、多柔比星（50mg/M²）和依托泊苷（240mg/M²）（CDE）进行96小时持续静脉输注并联合非格司亭用于治疗与HIV感染相关的非霍奇金淋巴瘤患者的可行性。同时还研究了沙奎那韦对CDE诱导的骨髓抑制、CD4淋巴细胞减少及非血液学毒性的影响。12例HIV相关淋巴瘤患者每28天或更长时间接受一次CDE治疗。所有患者均接受沙奎那韦（口服600mg，每日3次）、非格司亭以及卡氏肺孢子虫和真菌预防治疗。患者还接受了司他夫定（2例）或司他夫定与去羟肌苷联合治疗（10例）。使用美国国立癌症研究所通用毒性标准对每个周期的毒性进行分析，并将数据与我们之前关于CDE加去羟肌苷的研究数据进行比较。在纳入前12例患者后进行中期分析以评估毒性。接受CDE加沙奎那韦治疗的12例患者中有8例（67%）发生了严重（3级或4级）黏膜炎，而我们之前未使用沙奎那韦的CDE治疗研究中的25例患者中有3例（12%）发生黏膜炎（P<0.001）。在逻辑回归分析中，使用沙奎那韦是与严重黏膜炎风险显著增加相关的唯一因素（相对风险7.9；P=0.03）。使用沙奎那韦在发热性中性粒细胞减少症、中性粒细胞减少持续时间、化疗剂量减少或骨髓抑制程度的发生率方面无显著差异。接受沙奎那韦治疗的患者CD4淋巴细胞减少（绝对减少23/μL，或较基线下降26%）明显少于之前研究中未接受沙奎那韦治疗的患者（绝对减少91/μL，或较基线下降42%；P=0.05）。接受沙奎那韦治疗的10例患者中有4例（40%）CD4淋巴细胞增加≥10/μL，而未接受沙奎那韦治疗的25例患者中无一例增加（0%）（P<0.001）。蛋白酶抑制剂沙奎那韦与HIV相关淋巴瘤患者的CDE输注联合使用与严重黏膜炎发生率显著增加相关。这一发现提示沙奎那韦可能改变了CDE方案中一种或多种细胞毒性药物的代谢，并强调了在接受化疗的患者中使用蛋白酶抑制剂需要仔细研究。
