Annals of Oncology 9 (Suppl. 5): S115-SU9, 1998.
© 1998 Kluwer Academic Publishers. Primed in the Netherlands.
Review
Pediatric Hodgkin's disease: Treatment in the late 1990s
G. Schellong
University Children's Hospital Munster, Germany
procarbazine, prednisone, adriamycin) for girls and two cycles
of OEPA (etoposide instead of procarbazine) for boys. Patients
Background: For two decades now combined chemo-radio- of TG 2 and 3 additionally received two or four cycles of
therapy has been preferred in most of the studies on childhood COPP (C, cyclophosphamide), respectively. CT was followed
Hodgkin's disease (HD), because combined modality is the by radiotherapy to the involved sites (reduced fields if possible)
precondition for (1) reducing the radiation dose, (2) reducing of 25, 25 and 20 Gy in the 3 TG, respectively.
the radiation fields, (3) shortening chemotherapy, (4) omitting
Preliminary results: For the total group of 578 pats, overall
splenectomy and laparotomy, and thus, for optimizing the ben- survival (OS) at 5 years is 98% and event-free survival (EFS)
efit/risk ratio between cure rates and late effects. Recently, the 91%. In TG 1, EFS for girls (2 OPPA) is 96%, and for boys
rationale for this approach was strengthened by worrisome (OEPA), 94%, in TG 2 and 3 (combined), 92% and 86%,
data about the increasing incidence of secondary breast cancer respectively. Secondary leukemias were not observed so far.
in women treated for HD in childhood, adolescence or adult thirty-one male patients of TG 1 who were tested endocrinoage < 30 years. Nearly all breast cancers were localized in the logically showed normal FSH levels.
former radiation field, and the relative risk was much higher
Conclusions: The especially high efficacy of OPPA and
after doses >40 Gy than after lower doses. These findings OPPA/COPP could be confirmed in study HD-90 with reduced
suggest that pediatric therapy approaches abandoning radio- radiation doses and fields. OEPA and OEPA/COPP CT also
therapy alone with its high doses and large fields should be produced very favorable results, not significantly different from
extended to adolescents treated outside of pediatric studies those with OPPA and OPPA/COPP. It may be anticipated that
and to adults younger than 30. The risk of chemotherapy- the ratio beetween cure rates and risks of late effects of study
related secondary leukemias can be limited to < 1% by omit- HD-90 will compare favorably to approaches of other groups.
ting mechlorethamine and restricting the cumulative doses of
It would be useful for the future continued optimization of
other drugs with leukemogenic potential, as demonstrated by HD therapy to attain a rough consensus at an international
the experience with ABVD and the recently published data of level about principles which should be considered for pediatric
the German-Austrian pediatric group.
approaches. Some proposals have been made for treatment of
Patients and methods: The updated results of the German- early stages.
Austrian multicenter study HD-90 are presented in this paper
(578 patients < 18 years, follow-up: median 4 years, maximum
7 years). Patients were allocated to three treatment groups Key words: combined modality therapy, gonadal dysfunction
(TG) according to disease stage. In all three TG, induction after chemotherapy, OEPA, OPPA, secondary malignancies,
chemotherapy (CT) provided two cycles of OPPA (vincristine, treatment of Hodgkin's disease in childhood and adolescence
Summary
Introduction
Therapy-related second malignancies
At the Third International Symposium on Hodgkin's
Disease (HD) in Cologne 1995, two reviews about childhood HD [1, 2] demonstrated that the combination of
chemo- and radiotherapy is preferred in most of the
pediatric studies. Combined treatment modality is the
precondition for (1) reducing the radiation doses, (2)
reducing the radiation fields, (3) shortening chemotherapy, (4) omitting diagnostic splenectomy and laparotomy, and thus, for optimizing the benefit/risk ratio between cure rates and late effects. In this review more
recent publications and data as well as perspectives will
be discussed.
In 1996, worrisome data were reported in two publications showing high incidences of breast cancer in women many years after they had received radiotherapy for
HD in childhood and adolescence [3, 4], The analyses
confirmed earlier reports that secondary solid tumors
generally arise relatively late after therapy of HD, with
the incidence progressively increasing after 10 years [5].
The cumulative incidence of second tumors in the
cohort of 1380 patients of the Late Effects Study Group
(LESG) reached 12% after 20 years and continued to
increase thereafter [3]. Further, the two analyses added
the new aspect that breast cancer in females is increasingly predominant with ongoing follow-up time. The
116
Study HD-90: Therapy Plan
TG1: I.IIA
TG2.
a a
local RT
25 Gy*
local RTj
25 Gy*
IIB.IIIA
n
TG3IIIB-IV
(+IIEB. I
1-
I—'
5.
local RTl
gOGy*
9.
13.
17
21.
25.
week
OPPA (girts)
m pp
c ocopp
•
OEPA(boys)
•
* 10-15 Gy boost to sites with residual tumor after chemotherapy
ethamine was given to all patients. Primary chemotherapy consisted of OPPA /COPP and related combinations. The cumulative risk of secondary hematologic
malignancies in the total group was 0.7% after 10 years,
and 1.1% after 15 years and was thus in the same range
as after ABVD [11], but considerably lower than the
reported 3%-6% after treatment with MOPP [5, 8, 9].
Salvage therapy was the only significant risk factor. The
relatively low incidence of secondary leukemias in this
cohort has to be attributed mainly to the relatively low
cumulative doses of alkylating agents, especially to the
omission of mechlorethamine. Moreover, the low percentage of patients requiring salvage therapy (11%) is
also a relevant factor.
Figure I. Therapy plan of study HD-90 (see text).
The German-Austrian multicenter study DAL-HD-90
cumulative risk of breast cancer in the female patients of
the LESG shows a steady increase after the age of 25 has
been reached, arriving at a risk of 12% at 35 years of age.
There are additional events later on, but the calculated
values indicating very high risks at 40 years and thereafter are not very reliable, as the standard errors are
very large due to the small numbers of patients in this
age group. If the Stanford experience in combined cohorts of adult and childhood patients [6] is considered
jointly with the pediatric data of the LESG and the
Nordic countries [3, 4], it is evident that there are two
major risk factors: radiotherapy and age at the time of
treatment. Nearly all reported breast cancers were localized in the former radiation fields, and the incidence was
much higher after doses over 40 Gy than after lower
doses. Regarding age, the risk was highest in women
irradiated between 10 and 15 years of age and declined
with increasing age. The elevation remained significant
for females less than 30 years at the time of irradiation,
but was not detectable in those who received radiotherapy at age 30 or over. The combination of radiotherapy
with MOPP chemotherapy might be an additional risk
factor [6]. These findings are additional arguments in
favor of reducing the radiation doses and fields, which
has become common practice in most pediatric studies
within the framework of combination therapy [7]. The
findings also suggest that such approaches should be
extended to adolescents treated outside of pediatric
studies and even to young adults in order to abandon
radiotherapy alone with its high doses and large fields
for patients with early and favorable stages.
On the other hand, it has been proven that chemotherapy may increase the risk of secondary leukemias.
However, there is much evidence in the literature that
the leukemogenic potential of a chemotherapy combination depends largely on the cumulative total doses of
some critical cytotoxic agents such as mechlorethamine
and other alkylating agents [5, 8, 9]. In 1997, the German-Austrian pediatric study group published its data
on secondary leukemias in a cohort of 667 children
treated in four consecutive trials between 1978 and 1990
[10]. Combined chemo-radiotherapy without mechlor-
Patient entry in the German/Austrian multicenter trial
HD-90 [1, 12] was completed in 1995. As the median
follow-up is more than four years now (February 1998),
with a maximum of more than seven years, some preliminary conclusions can be drawn from this trial. This
was the fifth study of a consecutive series since 1978 in
which more than 90% of all children and some proportion of the adolescents with Hodgkin's disease in the two
countries have been treated. Seventy-two centers enrolled
a total of 578 study patients below age 18 with previously
untreated primary HD in study HD-90 between October
1990 and July 1995. The median age was 13.0 years; 319
were boys and 259 girls. As in our previous studies,
patients were stratified to three treatment groups (TG)
by disease stages. The size of the mediastinal mass and
other features were not used as additional criteria for
allocation.
Therapy
The comprehensive, risk-adapted treatment plan was
designed on the base of the experience gained from the
previous studies (Figure 1). The number of chemotherapy cycles in the three treatment groups (TG) was two,
four, and six, respectively. The two induction courses
comprised two cycles of vincristine, procarbazine, prednisone, and adriamycin (OPPA) for girls, and two times
OEPA for boys. In OEPA, etoposide (cumulative total
dose 1000 mg/m2) replaced the procarbazine of OPPA
[1, 12], in an attempt to reduce the risk of testicular
damage. In previous late effects studies, procarbazine
has been proven to be predominantly responsible for the
gonadal toxicity of OPPA and OPPA/COPP (C, cyclophosphamide) in male patients [13-15]. The risk was
dependent on the number of procarbazine-containing
cycles. By contrast, the same chemotherapy did not lead
to ovarian dysfunction in girls [16]. Patients in TG 1 of
study HD-90 had no further chemotherapy after two
cycles of OPPA or OEPA, whereas those in TG 2 and
TG 3 went on to receive two or four cycles of COPP in
addition. Chemotherapy was followed by local radio-
117
All
(a)
Stages
Event-free Survival.
Therapy Group 2*3
0.9ftSD=0.01
0.9!:SO=0.01
0.92;SD*0.02
O.BE:SO=0.03
— 0.6-
— 0.6 •
5
CD
o
P=0.11
Event-free Survival: N=57B, 48 events
N*578. 10 oeatns
Survival:
Event-free Survival,
(OEPA-COPP): N=160. 21 events
Girls
(0EPA«C0PP): N = U 3 ,
11 events
1.2.98
Figure 2. Kaplan-Meier curves of overall survival (OS) and event-free
survival (EFS) for the total patient group (« = 578) in study HD-90.
(a)
Boys
(b)
1.2.98
Survival. Therapy Group 2*3
0.97;SD=0.01
0.95:SD«0.02
Therapy Group 1
1.0 -
0.93:SD=0.02
0.91. SD=0.05
P=0.60
Boys
(OEPA-COPP): N=160.
4 events
Girls
(OPPA'COPP): NM43,
5 events
1.2.98
p=0 38
NM59.
11 events
Girls (OPPA)- N=116.
Boys (OEPA):
5 events
1.2.9B
Years
(b)
Survival.
Therapy Group 1
l.OftSB-O.OO
0.99:50=0.01
1 0-
p=0 40
Boys (OEPA): N=159.
1 events
GirlB(OPPA): N=116, 0 events
1.2.98
Years
Figure 3. Kaplan-Meier curves for girls (2 OPPA) and boys (2 OEPA)
in treatment group 1. (a) EFS, (b) OS.
therapy. The standard doses were 25, 25 and 20 Gy in
the three treatment groups, respectively. A local boost
up to 30-35 Gy was given to sites with lymphoma regression of less than 75% after chemotherapy. In patients
whose lymphomas were initially located only in part of
the classical fields, irradiation was confined to the involved sites, e.g., upper or lower neck, upper mediastinum, upper axilla, upper paraaortic regions, and so on
[17].'
Preliminary results
In the total group of 578 patients (girls and boys with all
stages), the probability for overall survival (OS) at five
years is 98%, and for event-free survival (EFS). 91%
(Figure 2). Age does not influence OS and EFS at all
[1, 12]. No secondary leukemias and MDS have been
Figure 4. Kaplan-Meier curves for girls (2 OPPA plus 2 or 4 COPP)
and boys (2 OEPA plus 2 or 4 COPP) in the combined treatment
groups 2 and 3. (a) EFS. (b) OS.
observed until now. Of course, it is too early to make
final conclusions about the leukemia risk. Nevertheless,
as the median interval for the appearance of leukemias
induced by topoisomerase II inhibitors such as etoposide
is two to three years [9, 18, 19] and the median follow-up
of the 578 patients already extends beyond four years, it
can now be supposed that the dose of 1,000 mg/m"
etoposide in the chemotherapy for boys will virtually
not increase the leukemia risk.
In TG 1, which includes the patients with stages I and
IIA (47.6% of all patients), the probabilities for EFS at
five years are 96% (girls) and 94% (boys; Figure 3). OS is
100% in both subgroups. A local boost up to 30-35 Gy
was given to 14% of the patients due to significant
residues after chemotherapy. Until now we have completed endocrinological tests in 31 male patients of this
group who had attained an age of 15 years or more. All
31 patients (who had received only two cycles of OEPA
chemotherapy) showed normal values of follicle stimulating hormon (FSH), as compared to 11 of 38 patients
with increased FSH levels after treatment with two cycles
of OPPA in previous studies. This difference is highly
significant (P = 0.006).
In the intermediate and advanced stages (TG 2 and 3)
EFS after five years is 92% (girls) and 86% (boys), and
OS 95% and 97%, respectively (Figure 4). The differences are not significant.
For the time being, the following conclusions can be
drawn from study HD-90:
- Radiotherapy, if combined with OPPA or OPPA/
COPP chemotherapy, can be confined to the ini-
118
tially involved sites (instead of involved fields) and
to doses of 20-25 Gy without compromising the
outcome as compared to earlier studies [1,12].
In localized stages (47.6% of patients) two cycles of
OEPA obviously have equal efficacy as two cycles
of OPPA. The risk of testicular dysfunction is
significantly lower after two OEPA than after two
OPPA.
In the more advanced stages, OEPA/COPP produces highly favorable results, not significantly
different from those with OPPA/COPP. However,
testicular dysfunction with germinal epithelial dysfunction has to be expected in a certain percentage
of the male patients due to the procarbazine in
COPP [13, 14].
After a median follow-up of four years (max. seven
years), no secondary leukemias have been observed.
It may be anticipated that the ratio between cure
rates and risks of late effects will be especially
favorable in study HD-90 (as compared to the
therapy concepts of other groups).
Future perspectives
It would be most desirable for the continued optimization of treatment schedules to attain a rough consensus
at an international level on principles to be considered
when treatment concepts for children and adolescents
with Hodgkin's disease are designed, perhaps extending
them to young adults. What such a consensus might look
like can best be demonstrated in the group of patients
with stages I and IIA. In the industrialized countries this
group comprises 40-50% of all patients, less in developing countries. We know that these patients have a 95% to
100% chance of long-term survival and cure, patients
with large mediastinal mass included. Thus, adverse
long-term effects of therapy are hardly acceptable in
this group, especially serious sequelae such as secondary
malignancies and cardiac problems [20, 21]. In order to
reduce the risks of late effects as much as presently
possible, it is necessary:
- to omit high-dose extended-field radiotherapy;
- to achieve rates of EFS (FFTF) higher than 90%,
because additional salvage therapy is one of the
highest risk factors for secondary malignancies
and other late effects [10, 22];
- to give short chemotherapy of 8-12 weeks duration,
• without mechlorethamine,
• without procarbazine in boys.
• with limited cumulative doses of other critical
drugs such as alkylating agents, anthracyclines,
bleomycin, etoposide;
- to give low-dose radiotherapy to the involved fields
or sites only. The percentage of patients needing a
local boost should not exceed 15%—20%;
- to abandon splenectomy.
Three national groups in Europe have tried to realize
Table 1. Chemotherapy (cumulative doses in mg/m 2 ) in four pediatnc
trials for stage I — II.
French
MDH-90[24]
Italian
MH-89[23]
German/Austrian
HD-90 [1, 12]
3 ABVD
2 OPPA
girls
2 OEPA
boys
4 VBVP
ADR
BLEO
DTIC
PC
VP16
VBL
VCR
PRED
150
60
2250
_
_
36
160
3000
9
1800
160
_
1000
_
9
I860
_
40
2000
48
1120
Duration
12 weeks
8 weeks
8 weeks
12 weeks
-
such postulates by using different chemotherapy schedules: in Italy, three cycles of ABVD over 12 weeks [23],
in the German-Austrian studies, two cycles of OPPA
for girls and two cycles of OEPA for boys over eight
weeks as described above, and in France, four cycles of
VBVP (vinblastine, bleomycin, VP16, prednisone) over
12 weeks [24]. Radiotherapy has been given to the involved fields or sites using 20-25 Gy with an additional
boost (and/or additional short chemotherapy) in 12%18% of the patients for significant lymphoma residues
after chemotherapy. There are 100 or more patients in
each of the four groups. The five-year Kaplan-Meier
estimates are 94%-96% for EFS and 97%-100% for
overall survival. The common denominator of the four
different schedules is the use of low cumulative doses of
drugs with possible late effects (Table 1). It may be
anticipated, or has already been proven on the basis of
existing data, that the risks for the different late effects
to occur with the four schedules are very low. Of course,
for final results a longer follow-up is needed.
It is more difficult to establish corresponding guidelines for the intermediate and advanced stages, but it
would still be feasible by comparative analyses of the
larger multicenter studies and their results.
Many single institutions and some cooperative groups
have tried to treat their patients with chemotherapy
alone in order to omit the late effects of radiotherapy.
As already pointed out by Oberlin [2], most of the
reported trials are associated with major problems such
as small patient groups and/or prolonged chemotherapy
with high risks of long-term toxicity. Principally, it has
already been known for 20 years now that a larger or
smaller percentage of the patients with all stages can be
cured with chemotherapy alone. However, the quality
and extent of chemotherapy needed to prevent unfavorable treatment results, increased late toxicity by compensating prolongation of chemotherapy included, has
not yet been established. Today there are many indications and even evidence from the literature that low-dose
radiotherapy to limited fields is associated with only low
risks of late effects, especially serious late effects [3, 20,
119
21, 25-27]. Consequently, the standards attained with
combined modality therapy should not be jeopardized
lightly. The era in which small innovative studies were
able to pioneer further development of HD therapy has
definitely passed. Today, already proven treatment concepts have to be further optimized step by step within
the framework of large and well organized multicenter
studies. This is the only way to obtain further progress.
Such studies may investigate if, for instance, specified
subgroups of the patients can be left without radiotherapy after a chemotherapy of low toxicity and high
efficacy. The current German-Austrian study HD-95
conducted by Dr. Dorffel in Berlin, which also includes
Swiss, Swedish and Dutch centers, may serve as an
example. The very same chemotherapy as in the previous
study HD-90, is used with two, four, or six cycles in the
three risk groups, respectively, but radiotherapy is omitted in those patients in whom the lymphomas have
completely disappeared after chemotherapy [28]. Some
years of experience with this approach will then form a
solid basis for the next step.
13.
14.
15.
16.
17.
18.
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Correspondence to:
Prof. Dr. G. Schellong
Univ.-Kinderklinik
Albert-Schweitzer-Str. 33
D-48129 Munster
Germany