Role of radiotherapy to bulky sites of advanced Hodgkin lymphoma treated with ABVD: final results of FIL HD0801 trial

Umberto Ricardi, Mario Levis, Andrea Evangelista, Daniela Maria Gioia, Gian Mauro Sacchetti, Manuel Gotti, Alessandro Re, Michela Buglione, Vincenzo Pavone, Antonio Nardella, Luca Nassi, Manuela Zanni, Paola Franzone, Giovanni Piero Frezza, Alessandro Pulsoni, Lavinia Grapulin, Armando Santoro, Luigi Rigacci, Gabriele Simontacchi, Monica Tani, Francesco Zaja, Elisabetta Abruzzese, Barbara Botto, Vittorio Ruggero Zilioli, Delia Rota-Scalabrini, Roberto Freilone, Giovannino Ciccone, Andrea Riccardo Filippi, Pier Luigi Zinzani, Umberto Ricardi, Mario Levis, Andrea Evangelista, Daniela Maria Gioia, Gian Mauro Sacchetti, Manuel Gotti, Alessandro Re, Michela Buglione, Vincenzo Pavone, Antonio Nardella, Luca Nassi, Manuela Zanni, Paola Franzone, Giovanni Piero Frezza, Alessandro Pulsoni, Lavinia Grapulin, Armando Santoro, Luigi Rigacci, Gabriele Simontacchi, Monica Tani, Francesco Zaja, Elisabetta Abruzzese, Barbara Botto, Vittorio Ruggero Zilioli, Delia Rota-Scalabrini, Roberto Freilone, Giovannino Ciccone, Andrea Riccardo Filippi, Pier Luigi Zinzani

Abstract

The role of consolidation radiotherapy (RT) for bulky lesions is controversial in patients with advanced-stage Hodgkin lymphoma who achieve complete metabolic response (CMR) after doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)-based chemotherapy. We present the final results of the Fondazione Italiana Linfomi HD0801 trial, which investigated the potential benefit of RT in that setting. In this phase 3 randomized study, patients with a bulky lesion at baseline (a mass with largest diameter ≥5 cm) who have CMR after 2 and 6 ABVD cycles were randomly assigned 1:1 to RT vs observation (OBS) with a primary endpoint of event-free survival (EFS) at 2 years. The sample size was calculated estimating an EFS improvement for RT of 20% (from 60% to 80%). The secondary end point was progression-free survival (PFS). One hundred sixteen patients met the inclusion criteria and were randomly assigned to RT or OBS. Intention-to-treat (ITT) analysis showed a 2-year EFS of 87.8% vs 85.8% for RT vs OBS (hazard ratio [HR], 1.5; 95% confidence interval [CI], 0.6-3.5; P = .34). At 2 years, ITT-PFS was 91.3% vs 85.8% (HR, 1.2; 95% CI, 0.5-3; P = .7). Patients in CMR randomly assigned to OBS had a good outcome, and the primary end point of a 20% benefit in EFS for RT was not met. However, the sample size was underpowered to detect a benefit of 10% or less, keeping open the question of a potential, more limited role of RT in this setting. This trial was registered at www.clinicaltrials.gov as #NCT00784537.

© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Study outline.
Figure 2.
Figure 2.
Patient flow diagram.
Figure 3.
Figure 3.
EFS from the time of randomization. Determined according to ITT (A) or PP (B) analysis.
Figure 4.
Figure 4.
PFS from the time of randomization. Determined according to ITT (A) or PP (B) analysis.
Figure 5.
Figure 5.
Survival, stratified by subgroup (PP analysis). EFS (A) and PFS (B).

References

    1. Aleman BM, Raemaekers JM, Tirelli U, et al. ; European Organization for Research and Treatment of Cancer Lymphoma Group . Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med. 2003;348(24):2396-2406.
    1. Fabian CJ, Mansfield CM, Dahlberg S, et al. . Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study. Ann Intern Med. 1994;120(11):903-912.
    1. Bonfante V, Santoro A, Viviani S, Valagussa P, Bonadonna G.. ABVD in the treatment of Hodgkin's disease. Semin Oncol. 1992;19(2 suppl 5):38-44; discussion 45.
    1. Laskar S, Gupta T, Vimal S, et al. . Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need? J Clin Oncol. 2004;22(1):62-68.
    1. Johnson PW, Sydes MR, Hancock BW, Cullen M, Radford JA, Stenning SP.. Consolidation radiotherapy in patients with advanced Hodgkin’s lymphoma: survival data from the UKLG LY09 randomized controlled trial (ISRCTN97144519). J Clin Oncol. 2010;28(20):3352-3359.
    1. Picardi M, De Renzo A, Pane F, et al. . Randomized comparison of consolidation radiation versus observation in bulky Hodgkin’s lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma. 2007;48(9):1721-1727.
    1. Aleman BM, Raemaekers JM, Tomiŝiĉ R, et al. ; European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group . Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2007;67(1):19-30.
    1. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. . Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109(5):1878-1886.
    1. Ng AK, Bernardo MP, Weller E, et al. . Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol. 2002;20(8):2101-2108.
    1. Schaapveld M, Aleman BM, van Eggermond AM, et al. . Second cancer risk up to 40 years after treatment for Hodgkin’s Lymphoma. N Engl J Med. 2015;373(26):2499-2511.
    1. Maraldo MV, Brodin NP, Aznar MC, et al. . Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann Oncol. 2013;24(8):2113-2118.
    1. Levis M, Filippi AR, Fiandra C, et al. . Inclusion of heart substructures in the optimization process of volumetric modulated arc therapy techniques may reduce the risk of heart disease in Hodgkin’s lymphoma patients. Radiother Oncol. 2019;138:52-58.
    1. Starke A, Bowden J, Lynn R, et al. . Comparison of butterfly volumetric modulated arc therapy to full arc with or without deep inspiration breath hold for the treatment of mediastinal lymphoma. Radiother Oncol. 2018;129(3):449-455.
    1. Hoppe BS, Flampouri S, Su Z, et al. . Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;84(2):449-455.
    1. Rechner LA, Maraldo MV, Vogelius IR, et al. . Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold. Radiother Oncol. 2017;125(1):41-47.
    1. Conway JL, Connors JM, Tyldesley S, et al. . Secondary breast cancer risk by radiation volume in women with Hodgkin Lymphoma. Int J Radiat Oncol Biol Phys. 2017;97(1):35-41.
    1. De Bruin ML, Sparidans J, van’t Veer MB, et al. . Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. J Clin Oncol. 2009;27(26):4239-4246.
    1. Engert A, Haverkamp H, Kobe C, et al. ; Arbeitsgemeinschaft Medikamentöse Tumortherapie . 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. Lancet. 2012;379(9828):1791-1799.
    1. Borchmann P, Haverkamp H, Diehl V, et al. . Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
    1. Gallamini A, Tarella C, Viviani S, et al. . Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin Lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018;36(5):454-462.
    1. Zinzani PL, Broccoli A, Gioia DM, et al. . Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin Lymphoma: final results of the phase II part of the HD0801 study. J Clin Oncol. 2016;34(12):1376-1385.
    1. Gallamini A, Rossi A, Patti C, et al. . Consolidation radiotherapy could be safely omitted in advanced Hodgkin Lymphoma with large nodal mass in complete metabolic response after ABVD: final analysis of the randomized GITIL/FIL HD0607 trial [published correction appears in J Clin Oncol. 2021;39(1):9]. J Clin Oncol. 2020;38(33):3905-3913.
    1. Cheson BD, Pfistner B, Juweid ME, et al. ; International Harmonization Project on Lymphoma . Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
    1. Juweid ME, Stroobants S, Hoekstra OS, et al. ; Imaging Subcommittee of International Harmonization Project in Lymphoma . Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25(5):571-578.
    1. Rigacci L, Puccini B, Broccoli A, et al. . Clinical characteristics of interim-PET negative patients with a positive end PET from the prospective HD08-01 FIL study. Ann Hematol. 2020;99(2):283-291.
    1. Press OW, Li H, Schöder H, et al. . US intergroup trial of response-adapted therapy for stage III to IV Hodgkin Lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: southwest oncology group S0816. J Clin Oncol. 2016;34(17):2020-2027.
    1. Johnson P, Federico M, Kirkwood A, et al. . Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374(25):2419-2429.
    1. Borchmann P, Haverkamp H, Lohri A, et al. . Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol. 2017;18(4):454-463.
    1. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. . Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34(3):235-243.
    1. van Nimwegen FA, Ntentas G, Darby SC, et al. . Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines. Blood. 2017;129(16):2257-2265.
    1. Maraldo MV, Giusti F, Vogelius IR, et al. ; European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group . Cardiovascular disease after treatment for Hodgkin’s lymphoma: an analysis of nine collaborative EORTC-LYSA trials. Lancet Haematol. 2015;2(11):e492-e502.
    1. Swerdlow AJ, Cooke R, Bates A, et al. . Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a National Cohort Study. J Clin Oncol. 2012;30(22):2745-2752.
    1. Radford J, Illidge T, Counsell N, et al. . Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015;372(17):1598-1607.
    1. André MPE, Girinsky T, Federico M, et al. . Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017;35(16):1786-1794.
    1. Fuchs M, Goergen H, Kobe C, et al. . Positron Emission Tomography-Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group. J Clin Oncol. 2019;37(31):2835-2845.
    1. Kumar A, Burger IA, Zhang Z, et al. . Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes. Haematologica. 2016;101(10):1237-1243.
    1. Qi S, Milgrom S, Dabaja B, et al. . Two distinct prognostic groups in advanced-stage Hodgkin lymphoma revealed by the presence and site of bulky disease [published correction appears in Blood Adv. 2021;5(13):2793]. Blood Adv. 2020;4(9):2064-2072.
    1. Engert A, Plütschow A, Eich HT, et al. . Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.
    1. Kelsey CR, Broadwater G, James O, et al. . Phase 2 study of dose-reduced consolidation radiation therapy in diffuse large B-Cell lymphoma. Int J Radiat Oncol Biol Phys. 2019;105(1):96-101.

Source: PubMed

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