Wilson Wyndham H, Grossbard Michael L, Pittaluga Stefania, Cole Diane, Pearson Deborah, Drbohlav Nicole, Steinberg Seth M, Little Richard F, Janik John, Gutierrez Martin, Raffeld Mark, Staudt Louis, Cheson Bruce D, Longo Dan L, Harris Nancy, Jaffe Elaine S, Chabner Bruce A, Wittes Robert, Balis Frank
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Blood. 2002 Apr 15;99(8):2685-93. doi: 10.1182/blood.v99.8.2685.
We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 x 10(9)/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = -0.54 and P(2) =.08 and r = -0.45 and P(2) =.034, respectively). Free-etoposide clearance increased significantly during successive cycles (P(2) =.015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P(2) =.04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.
我们推测，通过优化药物选择、给药方案和药代动力学，环磷酰胺-阿霉素-长春新碱-泼尼松（CHOP）化疗方案的逐步改进将改善大B细胞淋巴瘤患者的预后。对50例未经治疗的大B细胞淋巴瘤患者进行了一项前瞻性多机构研究，给予依托泊苷、长春新碱和阿霉素持续96小时，并静脉推注环磷酰胺和口服泼尼松（EPOCH疗法）。依托泊苷、阿霉素和环磷酰胺的剂量每个周期调整20%，以使最低点绝对中性粒细胞计数低于0.5×10⁹/L。患者的中位年龄为46岁（范围20 - 88岁）；24%的患者年龄大于60岁；根据国际预后指数（IPI）标准，44%的患者处于高中危或高危状态。92%的患者获得完全缓解，在中位随访时间62个月时，无进展生存期（PFS）和总生存期（OS）率分别为70%和73%。IPI危险因素及其指数本身均与缓解、PFS或OS无关。58%的周期中剂量得以递增，毒性水平可耐受。所有调整药物的剂量强度与年龄之间均观察到显著的负相关，阿霉素和游离依托泊苷的药物清除率也与年龄呈负相关（分别为r = -0.54，P₂ = 0.08和r = -0.45，P₂ = 0.034）。游离依托泊苷清除率在连续周期中显著增加（P₂ = 0.015）。增殖至少80%的淋巴瘤进展稍低，而表达bcl-2的淋巴瘤进展显著更高（P₂ = 0.04）。bcl-2的表达可能区分最近描述的活化B样和生发中心B样大细胞淋巴瘤，并提供重要的病理生物学和预后信息。剂量调整后的EPOCH可能比基于CHOP的方案产生更多的细胞杀伤作用。动态剂量调整可能克服药物浓度不足的问题，特别是在年轻患者中，并补偿随时间增加的药物清除。
