The Lancet：R-CHOP-21方案仍是新诊弥漫大B细胞淋巴瘤患者的标准一线方案

与每3周进行一次治疗的方案相比，将环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）方案剂量强化——每2周进行一次治疗，能改善60岁及以上的老年弥漫大B细胞淋巴瘤患者的预后。来自英国皇家Marsden基因会的David Cunningham等设计了相关研究，旨在确定当与利妥昔单抗联用时（R-CHOP），该剂量强化方案是否对所有年龄组的患者都能带来生存获益，他们的研究结果发表在The Lancet 4月的在线期刊上。

本研究所纳入的受试者为年龄在18岁及以上、既往没有接受过治疗的IA至IV期的弥漫大B细胞淋巴瘤患者，他们来自于英国的119个研究分中心。研究者将符合上述标准的受试者按照1:1的比例随机分为2组，R-CHOP-14组接受6个疗程的R-CHOP方案（每14天为1个疗程）联合2个疗程的利妥昔单抗治疗，R-CHOP-21组接受8个疗程的R-CHOP方案（每21天为1个疗程）。R-CHOP-21方案如下，第一天：按照环磷酰胺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的剂量静脉给药，第1-5天按照40mg/m2的剂量口服泼尼松，每21天为1个疗程，共计8个疗程。R-CHOP-14方案如下：第一天：按照环磷酰胺750mg/m2、多柔比星50mg/m2、长春新碱2mg和利妥昔单抗375mg/m2的剂量静脉给药，第1-5天口服泼尼松100mg，每14天为1个疗程，共计6个疗程，继之以375mg/m2的剂量继续应用利妥昔单抗，每14天为1个疗程，共计2个疗程。本研究未采用盲法。研究的主要结局为受试者的总体生存率。本研究已经进行注册，注册号为ISCRTN 16017947。

在研究中共纳入了1080名受试者，其中R-CHOP-21组为540人，R-CHOP-14组为540人。在进行了平均46个月的随访之后（IQR 35-57），2年总体生存率在R-CHOP-14组和R-CHOP-21组分别为82.7%和80.8%，HR为0.90，两组差异不具有显著统计学意义。同时，两组的2年无进展生存率也没有显著差异，在R-CHOP-14组和R-CHOP-21组分别为75.4%和74.8%，HR为0.94。研究者发现国际预后指数高、存在预后不良的分子学特征和细胞起源特征并不能预测受试者是否能从上述两种治疗方案中获益。在治疗所带来的不良反应方面，研究者发现在R-CHOP-21组中受试者更容易出现3及或4级的中性粒细胞减少，534名受试者中有318人（60%）发生，而在R-CHOP-14组的534名受试者中有167人（31%）发生，但是在R-CHOP-21组中并没有预防性使用重组人粒细胞集落刺激因子；而在R-CHOP-14组中出现3级或4级血小板减少的受试者更多，两组发生率分别为9%和5%；其他常见的3级或4级严重不良反应事件包括发热性中性粒细胞减少（R-CHOP-14/R-CHOP-21：11%/5%）和感染（R-CHOP-14/R-CHOP-21：23%/18%）。血液系统以外的不良反应事件在两组间的发生率相似。

本研究结果指出，对于既往没有接受过治疗的弥漫大B细胞淋巴瘤患者而言，R-CHOP-14方案的疗效并不优于R-CHOP-21方案。因此，在上述患者人群中，R-CHOP-21方案仍是标准的一线治疗方案。在本研究中，研究者并未发现分子学特征或临床特征不同的亚组受试者能从治疗的剂量强化中获益。
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Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Background
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.
Methods
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/m2, doxorubicin 50 mg/m2, vincristine 1·4 mg/m2 (maximum dose 2 mg), and rituximab 375 mg/m2 on day 1, and oral prednisolone 40 mg/m2 on days 1—5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg, rituximab 375 mg/m2 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/m2 on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947.
Findings
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.
Interpretation
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.
Funding
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.