ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)–Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial

doi:10.1016/j.ejca.2017.05.005

European Journal of Cancer

Volume 81, August 2017, Pages 45-55

https://doi.org/10.1016/j.ejca.2017.05.005 Get rights and content

Highlights

•
4 cycles of ABVD and IFRT 30Gy not inferior to 6-ABVD-IFRT in terms of efficacy.
•
4 cycles of BEACOPP_baseline have similar efficacy but more toxic than 4–6 ABVD.
•
4 cycles of ABVD is reference chemotherapy in early-stage HL with risk factors.

Abstract

Purpose

For early-stage Hodgkin lymphoma (HL), optimal chemotherapy regimen and the number of cycles to be delivered remain to settle down. The H9-U trial compared three modalities of chemotherapy followed by involved-field radiotherapy (IFRT) in patients with stage I-II HL and risk factors (NCT00005584).

Patients and methods

Patients aged 15–70 years with untreated supradiaphragmatic HL with at least one risk factor (age ≥ 50, involvement of 4–5 nodal areas, mediastinum/thoracic ratio ≥ 0.35, erythrocyte sedimentation rate (ESR) ≥ 50 without B-symptoms or ESR ≥ 30 and B-symptoms) were eligible for the randomised, open label, multicentre, non-inferiority H9-U trial. The limit of non-inferiority was set at 10% for the difference between 5-year event-free survival (EFS) estimates. From October 1998 to September 2002, 808 patients were randomised to receive either the control arm 6-ABVD-IFRT (n = 276), or one of the two experimental arms: 4-ABVD-IFRT (n = 277) or 4-BEACOPP_baseline-IFRT (n = 255).

Results

Results in the 4-ABVD-IFRT (5-year EFS, 85.9%) and the 4-BEACOPP_baseline-IFRT (5-year EFS, 88.8%) were not inferior to 6-ABVD-IFRT (5-year EFS, 89.9%): difference of 4.0% (90%CI, -0.7%–8.8%) and of 1.1% (90%CI,-3.5%–5.6%) respectively. The 5-year overall survival estimates were 94%, 93%, and 93%, respectively. Patients treated with combined modality treatment chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vincristine (Oncovin), cyclophosphamide, procarbazine, etoposide and prednisone (BEACOPP)_baseline more often developed serious adverse events requiring supportive measures and hospitalisation compared with patients receiving the chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD).

Conclusions

The trial demonstrates that 4-ABVD followed by IFRT yields high disease control in patients with early-stage HL and risk factors responding to chemotherapy. Although non-inferior in terms of efficacy, four cycles of BEACOPP_baseline were more toxic than four or six cycles of ABVD.

Introduction

In late 1990s, combined modality has become the standard of care for patients with stages I-II supradiaphragmatic Hodgkin lymphoma (HL) and risk factors [1], [2]. The risk-to-benefit ratio of therapy has remained a major challenge for physicians and patients. The European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group has investigated several risk-adapted strategies to distinguish between patient subgroups who might benefit from different approaches. Risk factors used in previous trials were applied to the H9 trial design [2], [3].

To optimise the treatment for stage I-II HL with risk factors, the randomised, open-label, multicentre, non-inferiority H9-U trial compared three chemotherapy modalities followed by involved-field radiotherapy (IFRT). The mechlorethamine, vincristine (Oncovin), procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, and vinblastine (MOPP-ABV) regimen [4] used in the H8-U trial [2] was replaced by the standard doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) regimen because the former was associated with more toxicity, particularly second malignancies [5]. In the early 1990s, weekly chemotherapy has been developed to improve disease control while shortening treatment duration [6]. The bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) regimen provided encouraging results [7]. At the point of time when the H9-U trial was initiated, the reference treatment was a combination of six cycles of ABVD and IFRT. It resulted in the comparison of two experimental combined modalities: four cycles of ABVD or BEACOPP_baseline followed by IFRT to six cycles of ABVD followed by IFRT. We report on the results of the EORTC-Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U trial for stage I-II HL with risk factors.

Section snippets

Patients

Patients aged 15–70 years with untreated stage I-II supradiaphragmatic classical HL with risk factors (age ≥ 50, stage II with 4–5 involved nodal areas, mediastinum/thoracic (M/T) ratio ≥ 0.35, no B-symptoms and erythrocyte sedimentation rate (ESR) ≥ 50 or B-symptoms and ESR ≥30) were eligible for the study (Fig. 1). Inclusion was based on the diagnosis made by local pathologists; the material was reviewed by a panel of pathologists (Appendix). Patients with lymphocyte-predominant nodular HL

Patients

Overall, 808 patients were categorized as having risk factors and enrolled in the H9-U trial from October 1998 to September 2002 (Fig. 1). Protocol violations occurred in 60 (7%) patients and were equally distributed between the three arms. Patient characteristics were well balanced between the three arms (Table 2).

Treatment delivery

Mean actual dose and relative dose-intensity delivered by chemotherapy regimen are given in Table 1. Overall, 85% of ABVD patients (4 or 6 cycles) and 67% of BEACOPP_baseline patients

Discussion

In patients with early-stage supradiaphragmatic HL and risk factors, the H9-U trial shows non-inferiority of both experimental arms (4-ABVD-IFRT or 4-BEACOPP_baseline-IFRT) to the reference arm (6-ABVD-IFRT). A combination of four cycles of ABVD and IFRT 30 Gy gives high disease control rate, with progression rate during treatment of 3.5%, and 5-year event-free and overall survival estimates of 86% and 93%, respectively.

Comparisons between 4-BEACOPP_baseline-IFRT and 6-ABVD-IFRT indicate that the

Conflict of interest statement

None declared.

Acknowledgments

We thank Catherine Fortpied of EORTC Head Quarters for advice on statistical analysis, and Chantal Rieux and Jacques Marnay of Centre François Baclesse, Caen, for technical assistance in the clinical and pathology data management. We are also grateful to the EORTC Charitable Trust for its support and we appreciate the contributions of the intergroup participating centres (Appendix).

The trial was supported by grants from the French Ministry of Health, Programme Hospitalier de Recherche Clinique

References (22)

T. Girinsky et al.
Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines
Radiother Oncol
(2006)
L. Specht et al.
Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG)
Int J Radiat Oncol Biol Phys
(2014)
A. Engert et al.
Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial
J Clin Oncol
(2007)
C. Fermé et al.
Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease
N Engl J Med
(2007)
E.M. Noordijk et al.
Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials
J Clin Oncol
(2006)
J.M. Connors et al.
Treatment of advanced Hodgkin's disease with chemotherapy-comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group
J Clin Oncol
(1997)
D.B. Duggan et al.
Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial
J Clin Oncol
(2003)
N.L. Bartlett et al.
Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: a preliminary report
J Clin Oncol
(1995)
V. Diehl et al.
BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group
J Clin Oncol
(1998)
C.K. Lee et al.
Prognostic significance of mediastinal involvement in Hodgkin's disease treated with curative radiotherapy
Cancer
(1980)

W.M. Hryniuk

Average relative dose intensity and the impact on design of clinical trials

Semin Oncol

(1987)

Cited by (31)

Harnessing multi-source data for individualized care in Hodgkin Lymphoma
2024, Blood Reviews
Hodgkin lymphoma is a rare, but highly curative form of cancer, primarily afflicting adolescents and young adults. Despite multiple seminal trials over the past twenty years, there is no single consensus-based treatment approach beyond use of multi-agency chemotherapy with curative intent. The use of radiation continues to be debated in early-stage disease, as part of combined modality treatment, as well as in salvage, as an important form of consolidation. While short-term disease outcomes have varied little across these different approaches across both early and advanced stage disease, the potential risk of severe, longer-term risk has varied considerably.
Over the past decade novel therapeutics have been employed in the retrieval setting in preparation to and as consolidation after autologous stem cell transplant. More recently, these novel therapeutics have moved to the frontline setting, initially compared to standard-of-care treatment and later in a direct head-to-head comparison combined with multi-agent chemotherapy.
In 2018, we established the HoLISTIC Consortium, bringing together disease and methods experts to develop clinical decision models based on individual patient data to guide providers, patients, and caregivers in decision-making. In this review, we detail the steps we followed to create the master database of individual patient data from patients treated over the past 20 years, using principles of data science. We then describe different methodological approaches we are taking to clinical decision making, beginning with clinical prediction tools at the time of diagnosis, to multi-state models, incorporating treatments and their response. Finally, we describe how simulation modeling can be used to estimate risks of late effects, based on cumulative exposure from frontline and salvage treatment.
The resultant database and tools employed are dynamic with the expectation that they will be updated as better and more complete information becomes available.
A rapid review of evidence and recommendations from the SIOPE radiation oncology working group to help mitigate for reduced paediatric radiotherapy capacity during the COVID-19 pandemic or other crises
2020, Radiotherapy and Oncology
Citation Excerpt :
Most protocols for the treatment of paediatric Hodgkin lymphoma have used 1.5–1.8 Gy fractions [26–28]. However, in adult Hodgkin lymphoma, 2 Gy fractions are standard [29]. In addition, the boost dose per fraction is also 2 Gy in the EuroNet protocol (level 2).
To derive evidence-based recommendations for the optimal utilisation of resources during unexpected shortage of radiotherapy capacity.
We have undertaken a rapid review of published literature on the role of radiotherapy in the multimodality treatment of paediatric cancers governing the European practise of paediatric radiotherapy. The derived data has been discussed with expert paediatric radiation oncologists to derive a hierarchy of recommendations.
The general recommendations to mitigate the potential detriment of an unexpected shortage of radiotherapy facilities include: (1) maintain current standards of care as long as possible (2) refer to another specialist paediatric radiotherapy department with similar level of expertise (3) prioritise use of existing radiotherapy resources to treat patients with tumours where radiotherapy has the most effect on clinical outcome (4) use chemotherapy to defer the start of radiotherapy where timing of radiotherapy is not expected to be detrimental (5) active surveillance for low-grade tumours if appropriate and (6) consider iso-effective hypofractionated radiotherapy regimens only for selected patients with predicted poor prognosis. The effectiveness of radiotherapy and recommendations for prioritisation of its use for common and challenging paediatric tumours are discussed.
This review provides evidence-based treatment recommendations during unexpected shortage of paediatric radiotherapy facilities. It has wider applications for the optimal utilisation of facilities, to improve clinical outcome in low- and middle-income countries, where limited resources continue to be a challenge.
Using both clinical research and population-based cancer registry in long-term research- a case study using EORTC trials and the Dutch national cancer registry (IKNL)
2020, Journal of Cancer Policy
Citation Excerpt :
The study was based on deterministic linkage of two large databases: The H1-H9 trials from the EORTC Lymphoma Group [9–16] Between 1964 and 2004, a total number of 6658 H L patients were enrolled into the H1-H9 trials, the first nine randomized phase III clinical trials of the EORTC Lymphoma group.
There are more than 12 million long-term survivors of cancer in Europe. Yet, research on outcomes of cancer treatment has not reached its full potential due to operational, regulatory and methodological constrains. The current study aims to show the complementary roles between clinical research and population-based cancer registry in this research field.
The authors used an empirical case study to show the level of agreement of variables between two databases of the same patients diagnosed with Hodgkin Lymphoma treated in the European Organisation for Research and Treatment of Cancer (EORTC) H1-H9 trials: one database is the clinical trial database from the EORTC and the other is the Netherlands Cancer Registry (IKNL).
The study showed a high level of agreement between the two datasets in most of the variables. However the vital status was more complete in the registry database, in particular for survivors diagnosed with cancer more than 10 years ago whereas treatment registration was more complete and in the EORTC clinical trial database.
The current case study is based on one single disease area and one cancer registry, which needs further research to prove its feasibility in other settings. Nevertheless the authors have envisagedseveral actionable collaboration activities between clinical research organizations and population-based registries in long-term outcome studies in the future, including data linkage, joint methodology development, data quality cross-check and improvement program.
Keep the Dose Low. Keep the Fields Tight
2020, International Journal of Radiation Oncology Biology Physics
Hodgkin lymphoma and target definition guidelines
2018, Cancer/Radiotherapie
Le traitement des lymphomes de Hodgkin de stades I/II repose sur la chimiothérapie et la radiothérapie. Ces associations thérapeutiques ont changé le pronostic et la survie des patients. Actuellement, la problématique est de diminuer leur toxicité. Grâce à la tomographie par émission de positons, essentielle dans la prise en charge initiale de ces lymphomes, la définition des volumes cibles en radiothérapie est devenue plus précise, ce qui a pu permettre une radiothérapie plus ciblée de type « involved node » ou « involved site ».
Treatment for stage I and II Hodgkin lymphoma is based on a combination of chemotherapy and radiotherapy, with a high successful cure rate. Now, the aim is to decrease toxicity rates. Positron-emission tomography scan is recommended as pretreatment baseline and is very useful to define precisely target volumes for planning radiation therapy. Based on these changes were developed guidelines for modern radiation therapy called involved node and « involved site ».
Radiation therapy planning for Hodgkin lymphoma: Focus on intensity-modulated radiotherapy, gating, protons. Which techniques to best deliver radiation?
2018, Cancer/Radiotherapie
L’optimisation de la radiothérapie dans la prise en charge d’un lymphome de Hodgkin localisé pose la question de l’intérêt d’utilisation des techniques modernes. Le choix de la technique d’irradiation doit tenir compte de l’incidence des effets secondaires en relation avec le rayonnement. Les recommandations internationales sur les champs de traitement reposent sur le concept « involved node radiotherapy ». La meilleure technique d’irradiation à utiliser reste à définir. L’utilisation de la radiothérapie avec modulation d’intensité permet d’améliorer la couverture et de diminuer la dose aux organes à risque, avec un gain variable en fonction de la topographie des ganglions : médiastin supérieur ou inférieur, latéralisation droite ou gauche, les techniques utilisées. L’inspiration bloquée entraîne une augmentation du volume pulmonaire, un allongement du médiastin avec un abaissement du cœur ce qui peut permettre d’éloigner le volume cible prévisionnel des structures cardiaques. L’arcthérapie volumétrique modulée (volumetric-modulated arc radiotherapy, VMAT) avec plusieurs arcs antérieurs peut être particulièrement intéressante pour réduire la dose aux seins, de même la tomothérapie lors d’atteintes étendues. La protonthérapie, compte tenu de la spécificité de pic de Bragg, peut jouer un rôle clé dans la limitation des doses délivrées aux organes à risque, sous réserve d’une planification robuste qui va prendre en compte les incertitudes géométriques et physiques. L’hétérogénéité de présentation clinique des lymphomes de Hodgkin concernant le volume, la forme et la localisation initiale sont les éléments clés à prendre un compte dans le choix de la technique de radiothérapie à privilégier.
The optimization of radiotherapy in these young and long-lived survivors raises the question about the interest of using modern techniques to allow a better distribution of the dose. The choice of the irradiation technique must take into account the incidence of side effects related to radiation. In this context, the definition of the target volumes as well as the verification and monitoring of the delivered processing are essential. International recommendations for treatment fields are based on the “involved node radiotherapy” concept. The best irradiation technique to use remains to be defined. The use of intensity-modulated radiotherapy improves the coverage and reduces the dose to the organs at risk with a variable gain depending on the topography of the lymph nodes: upper or lower mediastinum, right or left lateralization, the techniques used. The deep inspiration breath-hold technique allows an increase of the pulmonary volume, extension of the mediastinum with an up down of the heart which make possible to move the planning target volume away from the cardiac structures. The volumetric-modulated arctherapy technique with several arches can be particularly interesting to reduce the dose to the breasts, as well as tomotherapy when bulky disease. Proton therapy with the Bragg peak specificity can play a key role in limiting doses to organs at risk, when robust planning that will take into account geometric and physical uncertainties is available. The heterogeneity of Hodgkin lymphomas in terms of volume, shape and initial location are the key elements to take into account when choosing the preferred radiotherapy technique.

View all citing articles on Scopus

^☆: The study was presented in part at the 6th International Symposium on Hodgkin Lymphoma; September 18–21, 2004; Köln, Germany (Eur J Haematol 73:40–41 2004 [suppl 5; abstr E12]); the 2005 ASCO meeting (Proc Am Soc Clin Oncol 23:561, 2005 [abstr 6505]); the 47th Annual Meeting of the American Society of Hematology (ASH); December 10–13, 2005; Atlanta, Georgia, USA (Blood 106:240a, 2005 [abstr 813]); and the 7th International Symposium on Hodgkin Lymphoma; November 3–7, 2007; Cologne, Germany (Haematologica 92:27, 2007 [suppl 5; abstr C010]).

View full text

Original ResearchABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)–Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial☆

Highlights

Abstract

Purpose

Patients and methods

Results

Conclusions

Introduction

Section snippets

Patients

Patients

Treatment delivery

Discussion

Conflict of interest statement

Acknowledgments

Radiother Oncol

Int J Radiat Oncol Biol Phys

Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial

J Clin Oncol

Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease

N Engl J Med

Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials

J Clin Oncol

Treatment of advanced Hodgkin's disease with chemotherapy-comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group

J Clin Oncol

Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial

J Clin Oncol

Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: a preliminary report

J Clin Oncol

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group

J Clin Oncol

Prognostic significance of mediastinal involvement in Hodgkin's disease treated with curative radiotherapy

Cancer

Average relative dose intensity and the impact on design of clinical trials

Semin Oncol