Royal Marsden NHS Foundation Trust, London and Surrey, UK.
Lancet. 2013 May 25;381(9880):1817-26. doi: 10.1016/S0140-6736(13)60313-X. Epub 2013 Apr 22.
Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups.
Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947.
1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups.
R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study.
Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.
与每 3 周给予环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）的方案相比，每 2 周给予环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）联合方案可改善年龄超过 60 岁的弥漫性大 B 细胞淋巴瘤患者的结局。我们研究了在所有年龄组中，利妥昔单抗（R-CHOP）是否存在从剂量强化中获得的生存获益。
在英国 119 个中心，年龄≥18 岁且患有初治大肿块 I 期至 IV 期弥漫性大 B 细胞淋巴瘤的患者，采用中央随机分配，1:1 比例使用最小化方法，分别接受每 14 天 6 个周期的 R-CHOP 方案（R-CHOP-14）或每 21 天 8 个周期的 R-CHOP 方案（R-CHOP-21）。R-CHOP-21 为静脉注射环磷酰胺 750mg/m²、多柔比星 50mg/m²、长春新碱 1.4mg/m²（最大剂量 2mg）和利妥昔单抗 375mg/m²（第 1 天），同时口服泼尼松 40mg/m²（第 1-5 天），每 21 天重复，总共 8 个周期。R-CHOP-14 为静脉注射环磷酰胺 750mg/m²、多柔比星 50mg/m²、长春新碱 2mg 和利妥昔单抗 375mg/m²（第 1 天），同时口服泼尼松 100mg/m²（第 1-5 天），每 14 天重复，总共 6 个周期，然后在第 1 天每 14 天再静脉注射利妥昔单抗 375mg/m²，总共 2 个周期。该试验未设盲。主要结局为总生存（OS）。本研究注册于 ISRCTN 6017947。
1080 例患者被分配至 R-CHOP-21 组（n=540）和 R-CHOP-14 组（n=540）。中位随访 46 个月（IQR 35-57），R-CHOP-14 组和 R-CHOP-21（标准）组的 2 年 OS 分别为 82.7%（79.5-85.9）和 80.8%（77.5-84.2）（危险比 0.90，95%CI 0.70-1.15；p=0.3763）。2 年无进展生存（R-CHOP-14 组为 75.4%，71.8-79.1，R-CHOP-21 组为 74.8%，71.0-78.4；0.94，0.76-1.17；p=0.5907）也未见显著改善。高国际预后指数、不良预后分子特征和细胞起源均不能预测任何方案的获益。R-CHOP-21 组 3 级或 4 级中性粒细胞减少症（318[60%]例 534 例 vs 167[31%]例 534 例）发生率较高，该组未要求预防性使用重组人粒细胞集落刺激因子，而 R-CHOP-14 组 3 级或 4 级血小板减少症（50[9%]例 534 例 vs 28[5%]例 534 例）发生率较高；其他常见的 3 级或 4 级不良事件为发热性中性粒细胞减少症（58[11%]例 534 例 vs 28[5%]例 534 例）和感染（125[23%]例 534 例 vs 96[18%]例 534 例）。R-CHOP-21 组和 R-CHOP-14 组的非血液学不良事件发生率相似。
与每 21 天给予环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP-21）相比，每 14 天给予环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP-14）方案并不优于 R-CHOP-21 化疗，因此 R-CHOP-21 仍然是该血液恶性肿瘤患者的标准一线治疗方案。在这项研究中，没有分子或临床亚组从剂量强化中获益。
日本中外制药株式会社、英国癌症研究中心、英国国家卫生研究院生物医学研究中心（在伦敦大学学院和皇家马斯登 NHS 基金会信托基金）和英国癌症研究所。
