The EORTC strategy in the treatment of Hodgkin's lymphoma

Eur J Haematol 2005: 75 (Suppl. 66): 135–140
All rights reserved
Copyright Ó Blackwell Munksgaard 2005
EUROPEAN
JOURNAL OF HAEMATOLOGY
The EORTC strategy in the treatment of
Hodgkin’s lymphoma
Eghbali H, Raemaekers J, Carde P, EORTC Lymphoma Group. The
EORTC strategy in the treatment of Hodgkin’s lymphoma.
Eur J Haematol 2005: 75 (Suppl. 66): 135–140. Ó Blackwell Munksgaard
2005.
Houchingue Eghbali 1 , John
Raemaekers 2 , Patrice Carde 3 ,
EORTC Lymphoma Group
1 Current Chairman of the Lymphoma Group. Department
of Haematology, Institut BergoniØ, Bordeaux, France.
2 Former Chairman of the Lymphoma Group. Department
of Haematology, University Medical Centre, Nijmegen,
The Netherlands. 3 Department of Medical Oncology,
Institut Gustave Roussy, Villejuif, France.
The never ending discussion about the best treatment
of Hodgkin’s disease or lymphoma (HD) was
triggered and then fuelled because of the established
fact that this malignant disease is a priori a
curable one but leaving a high threat of complications
years after the end of the treatment. This
situation is the result of a stepwise approach
towards more treatment efficacy but surreptitiously
the debate moved from efficacy to treatment
dangers, changing the nature of the problem. The
EORTC lymphoma Group was also soon concerned
by this debate when the long-term survey of
patients in early trials demonstrated that the cure
rate could be high but the survival rate does not
eventually follow it closely and remains below that
of the general population. The discussion about
treatment complications was however conducted as
part of a global debate dealing at the same time
with staging and treatment efficacy, both for early
and advanced stages.
As for other cooperative groups dealing with
HD, the EORTC Lymphoma Group had to conduct
two distinct discussions about the so-called
early and advanced stages according to the Ann
Arbor classification, which is no longer adapted to
the current situation.
This debate went on during two periods with no
clear-cut limit between them. The first one from
1965 to 1987 (H1–H6) aimed at improving immediate
results and the second one from 1988 to 2003
and beyond towards lesser treatment toxicity (H7–
H9 and projected H10 for early stages, H3-4 for
advanced stages).
This strategy of reduction of treatment toxicity
has been running from the H7 trial started in the
late 1980s when it became obvious from the
previous trials that the main complications, cardiovascular
events and secondary cancers, were due to
the radiotherapy extent. However, as with every
investigator dealing with HD we had also in mind
the threat of acute leukaemia with the standard of
those days including MOPP and MOPP/ABV. For
the first time, with this trial a clinical prognostic
index was introduced to stratify very favourable
(VF), favourable (F) and unfavourable (U) early
stages, to abandon staging laparotomy and to
apply a tailored treatment to them (1, 2). These
prognostic factors included age (below or over
50 yr), systemic symptoms (A or B), erythrocyte
sedimentation rate (below or over 50 mm if A or 30
if B), and the number of involved areas based on
the radiotherapic fields (less or more than 3) and
finally mediastinum width over thorax ratio on the
chest X-ray (less or more than 0.35) (Table 1). If a
mantle field was the recommended treatment for
the VF group (young females with histology types 1
and 2 stage IA HD), in the favourable group (H7F)
the standard was an extended-field radiotherapy
(subtotal nodal irradiation, STNI), which was
compared to a brief non-leukaemogenic chemotherapy
(including epirubicin, bleomycin, vinblastin
and prednisone, EBVP) followed by involved-field
(IF) radiotherapy. In the unfavourable group
(H7U) the challenge was to compare the same
arm (6 EBVP + IF) to six courses of MOPP/
ABV + IF. For 5 yr 762 patients with clinically
staged supra-diaphragmatic HD were included in
this trial and treated according to their prognostic
group focused on maintaining the best survival and
reducing late effects. After a median follow-up of
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Eghbali et al.
6 yr, in the VF group there was a 23% rate of
relapses and 71% EFS. In the F group, the EFS
rate was 80% for STNI and 90% for EBVP + IF
(P ¼ 0.0228) without any difference in overall
survival (P ¼ 0.7) and in the U group, MOPP/
ABV + IF radiotherapy yielded a lesser proportion
of failures than EBVP + IF (99% vs. 77%).
Overall survivals were respectively 97%, 95%, and
83% for VF, F, and U groups (Table 2 and 3)
without any significant difference in different arms
(3, 4). These data were not available when the next
trial H8 was started in 1998. The objectives of this
trial were also a twin reduction of chemotherapy
and radiotherapy burden in order to reduce the late
treatment toxicity and maintain the EFS already
experienced previously. Based on these objectives
H8 had also STNI as standard in the favourable
group (H8F with 543 patients) and which was
compared to combined modality treatment using
three MOPP/ABV + IF (the same duration as for
H7F). In the unfavourable group (H8U with 995
patients) the standard was six courses of MOPP/
ABV + IF, compared to four MOPP/ABV + IF
Table 1. Prognostic factors in limited HD according to the EORTC Lymphoma Group
Criterion
Very
favourable (VF)
Favourable
(F)
Unfavourable
(U)
Age

The EORTC strategy in the treatment of Hodgkin’s lymphoma
based on our previous experience and we openly
wondered whether we could skip radiotherapy in a
subset of F patients in CR after chemotherapy or at
least lower the dose to 20 Gy in the same conditions
while 36 Gy remained the standard dose.
Patients who achieved partial remission were all
irradiated by IF at standard dose. In the H9U
group however the newly analysed BEACOPP
seemed promising for a higher rate of CR and then
a better survival for aggressive cases (8–10). This
regimen was compared to the standard with
ABVD, both arms having 30 Gy involved field
radiotherapy afterwards. We have currently no
mature data about this trial but some conclusions
are already available. In the H9F group the no
radiotherapy arm met the stopping rules (an
increased failure rate as compared to the radiotherapy
arms) 2 yr after its beginning (11) meaning
clearly that with the chosen (slight non-leukaemogenic)
chemotherapy, IF radiotherapy could not be
skipped. But it appeared also that radiotherapy
doses could be lowered to 20 Gy providing that the
complete remission is confirmed (by usual means,
CT and standard radiography). So far the EFS is
the same for 36 or 20 Gy (11). We need of course a
longer follow-up duration to confirm that this low
dosage after CR is enough to ensure the cure. And
if this is confirmed it would be a significant advance
in Hodgkin’s treatment and joins the German
group’s conclusions (12, 13).
In the H9U group, comparing three arms either
with 4 ABVD, 6 ABVD or with 4 BEACOPP all
followed by 30 Gy IF we have not yet all data to
draw a definitive conclusion. Although BEA-
COPP regimen showed very good results in
advanced and intermediate stages its potential
leukaemogenicity due to etoposide and cyclophosphamide
imposes a rather long follow-up.
But so far, in H9 the EFS rates are the same in
three arms (14).
How to go on and what is the next step? What is
then the crucial question in Hodgkin’s treatment?
Could we lower again the treatment intensity
without jeopardising the good results we have had
for more than 20 yr? These questions seem difficult
to answer for practical, ethical and strategic
reasons. The HD is a rare disease and a sensitive
one. Its evolution lasts for a long time even when
the treatment fails. Late complications appear more
than 15 yr after treatment has finished and patient
is cured, and often the physician who had taken
care of the patient is not the same one who meets
the late complication. Other parameters are new
techniques and new drugs, which change and
improve rapidly; they have to be taken into
account.
All these questions were debated among lymphoma
Group members and some conclusions are
emerging for the next steps and future treatment
strategy for limited stages of HD.
– First, the concept of prognostic factors has to be
reviewed. The previous prognostic system was
framed after a retrospective analysis of old trials
from 1965 to 1987 (1–7) and one could reasonably
believe that this system could no longer
work or would not fit the current technological
possibilities of imaging and radiotherapy or
recent advances in chemotherapy. Since this
system was framed we have had spread facilities
for Galium scintigraphy and especially and now
FDG–PET-scan and MRI that are not clearly
evaluated on a large scale or at least in controlled
trials. But there are accumulating data
that these techniques could better define the
(real) remission and distinguish an active mass
from a residual fibrous one (15–17). Now a
quick and early complete remission is considered
to be one of the most powerful prognostic factors
(in fact a surrogate Ôpredictive factorÕ), not
only in Hodgkin’s lymphoma but also generally
in haematology–oncology (18–20). Whether we
have to use other new prognostic factors, e.g.
eosinophilic infiltration, angiogenesis or cell
epitopes (21, 22) that is another matter of
debate, which cannot be put aside in the future.
– Second, recent advances in radiotherapy for
target definition and computerised dosimetry
allow to precise accurately the limits of the
radiotherapy fields and avoid other critical tissues,
especially those that should be protected,
e.g. heart, lung, spinal cord and even main
arteries.
– Third, even with adapted treatments some cases
whatever the group, respond slowly or partially
and are clinically in partial remission at the end
of chemotherapy. So far the treatment of the
early stages has been a global approach with
combined modality treatment. But if we want to
skip radiotherapy we have to be sure that the
remission is really complete. Otherwise this
incomplete remission has to be translated to a
complete remission Ôby any meansÕ. Such an
approach has proved to be effective in advanced
stages where partial remitters have an excellent
outcome close to that of complete remitters (23,
24).
Considering these three assumptions the next
trial H10 takes into account the prognostic value of
early response according to PET scan, the accurate
definition of radiotherapy fields (involved node
radiotherapy), and adversely the need of a more
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Eghbali et al.
aggressive and more extensive treatment in U cases
according to response and prognostic factors. All
early stages (still according to Ann Arbor criteria)
in the H10F group will be treated by a front line
chemotherapy, those who are not in CR after two
cycles of chemotherapy as determined by FDG–
PET scan, will be treated according to a different
scheme than those who are in CR. Early complete
remitters after two cycles of the front-line chemotherapy
will be treated with chemotherapy only in
the experimental arm, whereas the standard arm
still uses the combined modality treatment regardless
of the results of the FDG–PET scan after two
cycles. Those in the F10U group will have the same
approach with PET-scan but with more chemotherapy.
Hence in this trial the old prognostic
system is combined with a new dynamic factor,
namely early response, and radiotherapy fields and
dose are simultaneously discussed with a newly
definition of involved lymph node field instead of
involved area.
At the other side of the spectrum, in the
advanced stages the general trend was to intensify
the treatment burden to overcome disease aggressiveness.
The Lymphoma Group had compared
MOPP to alternating MOPP and ABVD followed
by optional radiotherapy (icebergs). This trial
aimed to compare the new concept of alternating
chemotherapy to the standard (MOPP), but there
was any addressed question about radiotherapy
(19). Later Cannellos and co-workers demonstrated
that this alternating scheme gives the same results
as hybrid MOPP/ABV and ABVD (25) leading to
the final conclusion that ABVD could be considered
as standard in advanced stages. The question
of radiotherapy’s role in patients with CR after
chemotherapy was raised by the EORTC Lymphoma
Group in its trial H3 and H4 (trial 20884).
All patients with stage III or IV had front line
MOPP/ABV. Those in CR after four courses had
two more cycles and were randomised between
24 Gy involved field radiotherapy and observation.
Others had four more cycles and were randomised
after eight courses in the same way. All partial
remitters were systematically irradiated on their
initial involved fields (40 Gy) and progressions
were put off-study. After a median follow-up of
8 yr it appeared that complete remitters had no
advantage from additional radiotherapy, complete
remission after efficacious chemotherapy proved to
be enough treatment in advanced stages (26, 27). In
this study however there was no selection according
to prognostic factors and F cases were treated in
the same way as the U ones. The retrospective
analysis according to Hasenclever and Diehl (28)
showed little help in dividing the very good and the
worst cases. The latter is commonly known to have
a very bad outcome. For a better result, if any, we
began a trial comparing eight cycles of standard
ABVD to an association of four escalated BEA-
COPP followed by four standard BEACOPP. This
inter-group trial in conjunction with the GELA and
other international collaborative groups (Nordic
group, NCI Canada, British BNLI, Australian
Lymphoma Group, Spanish Groups GELCAB
and PETHEMA) is currently running.
However, all these trials in early stages or
advanced stages use old drugs and even old
regimens. The AVBD was framed by Bonadonna
more than 30 yr ago (29) and nothing else since has
made this regimen obsolete. Every physician dealing
with HD knows its advantages and its toxicity
and limits. New regimes are probably needed. Here
also the limit is the high rate of cure, which makes
any trial in standard cases non-ethical. In the
elderly however there is a subset of patients with
aggressive HD (stages III and IV) that is unable to
have BEACOPP, at least with full dosage. For such
patients, the Lymphoma Group in collaboration
with the German Hodgkin Study Group began a
trial using gemcitabine instead of bleomycin and
prednisone instead of dacarbazine in the ABVD
regimen. Whether this new regimen (named PVAG)
with this new drug will be effective and non-toxic is
too early to know since this subset is very rare and
the trial too recent.
The HD is a continuous challenge for our minds. It
was a long time ago the scheme of combined
modality treatments in oncology for solid tumours
and still remains a leading example of treatment
management, for a better treatment combining lesser
toxicity and more efficacy. The EORTC Lymphoma
Group is deeply involved in this and currently has
joined other groups to face new challenges that
appear recently along with new social, economic,
medical, and politic conditions (30).
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