4周期R-CHOP治療侵襲性B細胞淋巴瘤患者的預後不劣於6周期R-CHOP
作者：
小柯機器人發布時間：2019/12/20 15:16:00
2019年12月21日，德國薩爾蘭大學醫學院Viola Poeschel聯合Westpfalz-Klinikum醫院Gerhard Held研究團隊在《柳葉刀》雜誌發表論文，比較了4周期或6周期CHOP化療+6劑利妥昔單抗治療侵襲性B細胞淋巴瘤患者的預後。
六個周期的R-CHOP（利妥昔單抗+環磷醯胺+阿黴素+長春新鹼+潑尼松）是治療侵襲性B細胞非霍奇金淋巴瘤的標準方案。在先前的試驗中，研究組發現四個周期CHOP聯合六個周期利妥昔單抗治療B細胞非霍奇金淋巴瘤的預後不劣於六個周期的R-CHOP治療。
2005年12月2日至2016年10月7日，研究組在丹麥、以色列、義大利、挪威和德國的138個臨床試驗點進行了一項雙臂、開放標籤、國際性、多中心、前瞻性、隨機、臨床3期的非劣效性試驗，共招募了592名18-60歲的B細胞非霍奇金淋巴瘤患者，I-II期，血清乳酸脫氫酶水平正常，ECOG表現狀態0-1，最大腫瘤直徑小於7.5釐米。將其按1：1隨機分組，其中295名患者接受6個周期的R-CHOP方案治療，297名患者接受4個周期的R-CHOP+2劑利妥昔單抗方案治療。
共有588名患者納入最終的意向治療分析。中位隨訪66個月後，4周期R-CHOP+2劑利妥昔單抗組的3年無進展生存率為96%，比6周期R-CHOP組好3%，符合非劣效性標準。4周期組共發生294例血液學和1036例非血液學不良事件，6周期組則分別為426例和1280例。6周期組中有2名患者在治療期間死亡。
總之，對於侵襲性B細胞非霍奇金淋巴瘤的年輕患者，4周期R-CHOP治療的預後不劣於6周期R-CHOP，且毒性顯著降低，值得臨床推廣。
附：英文原文
Title: Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial
Author: Viola Poeschel, Gerhard Held, Marita Ziepert, Mathias Witzens-Harig, Harald Holte, Lorenz Thurner, Peter Borchmann, Andreas Viardot, Martin Soekler, Ulrich Keller, Christian Schmidt, Lorenz Truemper, Rolf Mahlberg, Reinhard Marks, Heinz-Gert Hoeffkes, Bernd Metzner, Judith Dierlamm, Norbert Frickhofen, Mathias Haenel, Andreas Neubauer, Michael Kneba, Francesco Merli, Alessandra Tucci, Peter de Nully Brown, Massimo Federico, Eva Lengfelder, Alice di Rocco, Ralf Trappe, Andreas Rosenwald, Christian Berdel, Martin Maisenhoelder, Ofer Shpilberg, Josif Amam, Konstantinos Christofyllakis, Frank Hartmann, Niels Murawski, Stephan Stilgenbauer, Maike Nickelsen, Gerald Wulf, Bertram Glass, Norbert Schmitz, Bettina Altmann, Markus Loeffler, Michael Pfreundschuh
Issue&Volume: 2019/12/21
Abstract:
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18–60 years, with stage I–II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0–1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m 2), doxorubicin (50 mg/m 2), and vincristine (1·4 mg/m 2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1–5. Rituximab was given at a dose of 375 mg/m 2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of −5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42–100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94–99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
DOI: 10.1016/S0140-6736(19)33008-9
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)33008-9/fulltext