Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas:: a randomised controlled trial (RICOVER-60)
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas:: a randomised controlled trial (RICOVER-60)
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DOI：
10.1016/s1470-2045(08)70002-0
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发表时间：
2008-02-01
期刊：
影响因子：
51.1
通讯作者：
Loeffler, Markus
中科院分区：
文献类型：
--
作者：
Pfreundschuh, Michael;Schubert, Joerg;Loeffler, Markus
背景环磷酰胺、阿霉素、长春新碱和强的松龙(CHOP)用于治疗非霍奇金淋巴瘤。治疗间隔从3周(CHOP-21)减少到2周(CHOP-14)，在CHOP-21(R-CHOP-21)的基础上加用利妥昔单抗(R-CHOP-21)可以改善老年弥漫性大B细胞淋巴瘤(DLBCL)的预后。方法1222例年龄61~80岁的老年患者随机分为6个或8个周期的CHOP-14加或不加利妥昔单抗。放射治疗计划在有或无结外受累的初始大块病变部位进行。主要终点是无事件存活率；次要终点是反应、治疗过程中的进展、无进展存活率、总存活率和毒副作用发生的频率。根据治疗意向进行分析。该试验在国家癌症研究所网站上注册，编号为NCT00052936，编号为EU-20243。研究发现，CHOP-14 6周期后的3年无事件生存率为47.2%(95%CI 41.2-53.3)，CHOP-14 8周期后的3年无事件生存率为53.0%(47.0-59.1)，R-CHOP-14 6周期后的66.5%(60.9-72.0)，R-CHOP-14 8周期后的63.1%(57.4-68.8)。与6个周期的CHOP-14相比，CHOP-14 8个周期的3年无事件生存率提高5.8%(-2.8~14.4)，R-CHOP-14的6个周期提高19.3%(11.1-27.5)，R-CHOP-14的8个周期提高15.9%(7-6-24.2)。CHOP-14 6周期、CHOP-14 8周期、R-CHOP-14 6周期、R-CHOP-14 8周期总生存率分别为67.7%(62.0-73.5)、66.0%(60.1-71.9)、78-1%(73.2-83.0)、72.5%(67.1-77.9)。与CHOP-14治疗6周期相比，CHOP-14治疗8周期后总存活率提高-1.7%(-10.0-6.6)，R-CHOP-14治疗6周期提高10.4%(2.8-18.0)，R-CHOP-14治疗8周期提高4.8%(-3.1-12.7)。在一项多因素分析中，使用6个周期的CHOP-14作为参考，并调整已知的预后因素，所有3个强化方案都提高了3年无事件生存率(8个周期的CHOP-14：RR[相对风险]0.76[0.60-0-951，p=0.0172；6个周期的R-CHOP-14：RR 0-51[0.40-0.651，p&t；0.0001；8个周期的R-CHOP-14：RR 0.54[0，43-0.691，p<；0.0001])。经过6个周期的R-CHOP-14(RR0-50[0.38-0.67]，p<；0.0001)和8个周期的R-CHOP-14(RR0-59[0.45-0.77]，p=0.0001)，无进展生存率提高。总生存率仅在R-CHOP-14治疗6个周期后才有改善(RR0-63[0.46-0.85]，p=0.0031)。在化疗4个周期后部分缓解的患者中，8个周期并不比6个周期更好。解释6个周期的R-CHOP-14显著改善了6个周期的CHOP-14治疗的无事件、无进展和总存活率。反应适应增加化疗超过六个周期，虽然被广泛实践，但并不合理。在这项研究中评估的四种方案中，六个周期的R-CHOP-14是老年患者的首选治疗方案，其他方案应该与之进行比较。
Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14.Methods 1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243.Findings 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% Cl 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7-6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78-1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by-1.7% (-10.0-6.6) after eight cycles of CHOP-14,10.4% (2.8-18.0) after six cycles of R-CHOP-14,and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximah as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0 76 [0.60-0 - 951, p=0.0172; six cycles of R-CHOP-14: RR 0 - 51 [0.40-0.651, p < 0.0001; eight cycles of R-CHOP-14: RR 0 54 [0,43-0.691, p < 0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0 - 50 [0.38-0.67], p < 0.0001), and eight cycles of R-CHOP-14 (RR 0 - 59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0 - 63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles.Interpretation Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.