Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial

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• 作者：Andreas Engert ; MD^a ; ^b ; ^{a.engert@uni-koeln.de} ; Heinz Haverkamp ; PhD^b ; ^* ; Carsten Kobe ; MD^c ; ^* ; Jana Markova ; MD^d ; Christoph Renner ; MD^e ; Antony Ho ; MD^f ; Jos&eacute ; e Zijlstra ; MD^g ; Zdenek Krá ; l ; MD^h ; Michael Fuchs ; MD^b ; Michael Hallek ; MD^a ; Lothar Kanz ; MDⁱ ; Hartmut Dö ; hner ; MD^j ; Bernd Dö ; rken ; MD^k ; Nicole Engel ; MD^l ; Max Topp ; MD^m ; Susanne Klutmann ; MDⁿ ; Holger Amthauer ; MD^o ; Andreas Bockisch ; MD^p ; Regine Kluge ; MD^q ; Clemens Kratochwil ; MD^r ; Otmar Schober ; MD^s ; Richard Greil ; MD^t ; Reinhard Andreesen ; MD^u ; Michael Kneba ; MD^v ; Michael Pfreundschuh ; MD^w ; Harald Stein ; MD^x ; Hans Theodor Eich ; MD^y ; Rolf-Peter Mü ; ller ; MD^y ; Markus Dietlein ; MD^c ; Peter Borchmann ; MD^b ; Volker Diehl ; MD^b ; on behalf of the German Hodgkin Study Group ; the Swiss Group for Clinical Cancer Research ; the Arbeitsgemeinschaft Medikamentö ; se Tumortherapie^&dagger ;
• 刊名：The Lancet
• 出版年：2012
• 期刊代码：182_01406736
• 类别：med
• 出版时间：12-18 May, 2012
• 卷：379
• 期：9828
• 页码：1791-1799
• 文件大小：326 K

摘要

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Summary

Background

The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy.

Methods

In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP_escalated (8脳B_esc group), six cycles of BEACOPP_escalated (6脳B_esc group), or eight cycles of BEACOPP₁₄ (8脳B₁₄ group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2路5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041.

Findings

Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8脳B_esc group, 711 in the 6脳B_esc group, and 710 in the 8脳B₁₄ group. Freedom from treatment failure was sequentially non-inferior for the 6脳B_esc and 8脳B₁₄ groups as compared with 8脳B_esc. 5-year freedom from treatment failure rates were 84路4%(97路5%CI 81路0-87路7) for the 8脳B_esc group, 89路3%(86路5-92路1) for 6脳B_esc group, and 85路4%(82路1-88路7) for the 8脳B₁₄ group (97路5%CI for difference between 6脳B_esc and 8脳B_esc was 0路5-9路3). Overall survival in the three groups was 91路9%, 95路3%, and 94路5%respectively, and was significantly better with 6脳B_esc than with 8脳B_esc (97路5%CI 0路2-6路5). The 8脳B_esc group showed a higher mortality (7路5%) than the 6脳B_esc (4路6%) and 8脳B₁₄ (5路2%) groups, mainly due to differences in treatment-related events (2路1%, 0路8%, and 0路8%, respectively) and secondary malignancies (1路8%, 0路7%, and 1路1%, respectively). The negative predictive value for PET at 12 months was 94路1%(95%CI 92路1-96路1); and 225 (11%) of 2126 patients received additional radiotherapy.

Interpretation

Treatment with six cycles of BEACOPP_escalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP_escalated should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting.

Funding

Deutsche Krebshilfe and the Swiss Federal Government.