VOLUME 28 䡠 NUMBER 23
JOURNAL OF CLINICAL ONCOLOGY
From the Martin-Luther-University of
Halle-Wittenberg, Halle; HELIOS Klini-
kum Berlin-Buch; Charité-Berlin Univer-
sity Medical Centre, Campus Benjamin
Franklin, Berlin; Campus Kiel, University
of Schleswig-Holstein, Kiel; University
of Leipzig, Leipzig; University of
Schleswig-Holstein, Schleswig-Holstein,
Germany; Medical University of Vienna;
St Anna Children’s Hospital, Vienna,
Austria; Karolinska University Hospital,
Stockholm, Sweden; University Hospital
of Zurich, Zurich, Switzerland; and
Norwegian Radium Hospital, Oslo
University Hospital, Oslo, Norway.
Submitted November 6, 2009; accepted
April 28, 2010; published online ahead
of print at www.jco.org on July 12,
2010.
Written on behalf of the German
Society of Pediatric Oncology and
Hematology–Hodgkin’s Disease Study
Group.
Supported by grants from the Peter
Escher Foundation for Children With
Cancer, Menschen für Kinder, Hand
in Hand for Children, the Lions
Kinderkrebs-Forschungs und Ausbil-
dungszentrum, and the Deutsche
Krebshilfe (M.S.).
Both C.M.-K. and D.H. contributed
equally to the work.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Clinical Trials repository link available on
JCO.org.
Corresponding author: Christine Mauz-
Körholz, MD, Department of Paediat-
rics, Martin-Luther University of
Halle-Wittenberg, Ernst-Grube-Straße
40, D-06120 Halle (Saale); e-mail:
christine.mauz-koerholz@medizin
.uni-halle.de.
© 2010 by American Society of Clinical
Oncology
0732-183X/10/2823-3680/$20.00
DOI: 10.1200/JCO.2009.26.9381
3680 © 2010 by American Society of Clinical Oncology
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Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
䡠 AUGUST 10 2010
O R I G I N A L R E P O R T
Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys
and Standard OPPA-COPP in Girls Have Comparable
Effectiveness in Pediatric Hodgkin’s Lymphoma: The
GPOH-HD-2002 Study
Christine Mauz-Körholz, Dirk Hasenclever, Wolfgang Dörffel, Kathrin Ruschke, Tanja Pelz, Antje Voigt,
Martina Stiefel, Melanie Winkler, Constanze Vilser, Karin Dieckmann, Jonas Karlén, Eva Bergsträsser,
Alexander Fosså, Georg Mann, Michael Hummel, Wolfram Klapper, Harald Stein, Dirk Vordermark,
Regine Kluge, and Dieter Körholz
A B S T R A C T
Purpose
Vincristine, etoposide, prednisone, and doxorubicin (OEPA)– cyclophosphamide, vincristine, pred-
nisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone,
and doxorubicin (OPPA)– cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)
chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less
gonadotoxic regimen for boys with Hodgkin’s lymphoma (HL).
Patients and Methods
Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German
Society of Pediatric Oncology and Hematology–Hodgkin’s Disease (GPOH-HD) -2002 study
between November 2002 and December 2005. Boys received two courses of OEPA and girls
received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and
TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC
(boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8
Gy, except for patients with early-stage disease (TG-1) in complete remission.
Results
Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and
fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were
allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was
tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was
less pronounced with COPDAC compared with COPP. The median observation time was 58.6
months. Overall survival and event-free survival (EFS) rates (⫾ SE) at 5 years were 97.4% ⫾ 0.7%
and 89.0% ⫾ 1.4%, respectively. In TG-1, overall EFS was 92.0% ⫾ 2.0%. EFS of patients without
irradiation (93.2% ⫾ 3.3%) was similar to that of irradiated patients (91.7% ⫾ 2.5%), confirming
results of the previous GPOH-HD-95 study. In TG-2⫹3, EFS did not significantly differ between
boys and girls (90.2% ⫾ 2.3 v 84.7% ⫾ 2.7, respectively; P ⫽ .12).
Conclusion
In TG-2⫹3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be
exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.
J Clin Oncol 28:3680-3686. © 2010 by American Society of Clinical Oncology
are allocated to three treatment groups (TGs)
INTRODUCTION
based on early- (TG-1), intermediate- (TG-2), and
The German Society of Pediatric Oncology and advanced-stage (TG-3) disease. All patients start
Hematology–Hodgkin’s Disease (GPOH-HD) -2002 with two intensive induction cycles of chemothe-
study is the seventh in a series of treatment optimi- rapy (vincristine, procarbazine, prednisone, and
zation studies for pediatric patients with Hodgkin’s doxorubicin [OPPA] or variants). In TG-2 and
lymphoma (HL) started by Günther Schellong in TG-3, two or four consolidation cycles (cyclo-
1978.1-6 All seven studies evolved from a common phosphamide, vincristine, procarbazine, and pre-
combined-modality treatment scheme. Patients dnisone [COPP] or variants) are given, respectively.
 Procarbazine-Free Treatment in Pediatric Hodgkin’s Lymphoma
Radiotherapy follows after completion of chemotherapy. The treat-
ment results of the Deutschen Arbeitsgemeinschaft für Leukämiefor-
schung (DAL)/GPOH-HD trials have been generally excellent, with
event-free survival (EFS) rates of approximately 90% at 5 years in all
TGs.1-7 However, the long-term outcome after 20 years truly reflects
the HL treatment effects on morbidity and mortality.8,9 Thus, the
consecutive studies focused on reducing long-term toxicity. Without
compromising the treatment results, radiotherapy was reduced in
volume (from extended field to involved field) and in doses (from
36 to 20 Gy) to prevent growth impairment, lung dysfunction,
hypothyroidism, cardiac diseases, and secondary malignan-
cies.10-13 The GPOH-HD-95 study established that radiotherapy
can be safely omitted in TG-1 patients achieving complete remis-
sion after chemotherapy.6
Procarbazine is a major drug in both the OPPA and COPP
regimens and is known to be gonadotoxic.14 Cumulative doses of
procarbazine15,16 correlate with increasing rates of male infertility after
treatment. An attempt to eliminate procarbazine from OPPA and
replacement of procarbazine by low-dose methotrexate in COPP led
to an unacceptable decrease in efficacy in the third study generation.3
Thus, procarbazine had to be substituted by an equipotent drug. In the
fifth study generation, DAL-HD-90, boys received vincristine, etopo-
side, prednisone, and doxorubicin (OEPA; procarbazine in OPPA
replaced by a total etoposide dose of 500 mg/m2 within 4 consecutive
days) to preserve fertility.5 With this regimen, the outcome in boys
was nearly comparable to that in girls. Fertility was preserved in
early-stage male patients. However, follicle-stimulating hormone
(FSH) levels, which were used as a fertility surrogate marker, were still
elevated in males with intermediate- and advanced-stage disease
treated with COPP.5,15
In the GPOH-HD-95 study, boys had significantly worse
5-year disease-free survival rates than girls (0.86% v 0.93%, respec-
tively; P ⫽ .005). This was probably related to procarbazine replace-
ment by etoposide in OEPA for boys. In addition, male sex has been an
unfavorable prognostic factor in the adult setting and is considered
unfavorable in the International Prognostic Score.17
Nevertheless, in GPOH-HD-2002, a procarbazine-free regimen
for boys was prioritized because of gonadotoxicity. This resulted in the
plan to escalate the etoposide dose in the OEPA regimen to optimize
disease control. Etoposide administration was extended from 4 to 5
days (OE*PA), leading to a cumulative dose of 1,250 mg/m2 etoposide
in both cycles. This dose is below the critical dose of 2,000 mg/m2,
above which an increased risk of secondary acute myeloid leukemia
(AML) has been described.18-20
To eliminate oral procarbazine completely from treatment in
boys, procarbazine in COPP was replaced by intravenous (IV) dacar-
bazine, resulting in the cyclophosphamide, vincristine, prednisone,
and dacarbazine (COPDAC) regimen. Like procarbazine, dacarba-
zine acts as an alkylator and inhibits both DNA and RNA synthesis.
Within the doxorubicin, bleomycin, vinblastine, and dacarbazine
(ABVD) regimen, dacarbazine has been studied extensively in HL, and
it has been shown that male patients have a low probability of becom-
ing permanently azoospermic with this regimen.21,22 Earlier studies
on single-drug administration with either dacarbazine23,24 or pro-
carbazine25 report similar objective response rates, suggesting
equal effectiveness of dacarbazine 750 mg/m2 in ABVD compared
with procarbazine 1,800 mg/m2 in COPP. Thus, dacarbazine doses of
250 mg/m2 on days 1 to 3 in 30-minute infusions were considered
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Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
equivalent to a cumulative oral procarbazine dose of 1,500 mg/m2 in
the COPP cycle. The primary objective of this study was to show
feasibility and effectiveness of OE*PA-COPDAC in boys compared
with standard OPPA-COPP in girls.
PATIENTS AND METHODS
Patients and Study Design
From November 15, 2002 until December 31, 2005, the study recruited
660 consecutive patients with HL. The 97 trial sites in Germany, Austria,
Switzerland, Sweden, Netherlands, and Norway were committed to enroll all
pediatric patients with HL exclusively onto this study. Cross-check with the
German Childhood Cancer Registry showed that approximately 98% of all
German children up to 15 years old with HL were entered onto this study.26-28
Children and adolescents up to 18 years old with confirmed histology of
either classical or lymphocyte-predominant HL (LPHL) were enrolled onto
the study. Main exclusion criteria were relapse of HL, HL as secondary malig-
nancy, prior chemotherapy or radiotherapy (except corticosteroid prophase
for large mediastinal mass), and simultaneous comorbidity rendering the
protocol treatment unfeasible. The study protocol was approved by the Ethics
Committee of the University of Leipzig and by the respective institutional
review boards of the participating trial sites. Patients and/or their guardians
gave informed consent.
The histopathologic diagnosis was based on biopsy of a lymph node or of
another involved organ. Reference pathology was required including subtyp-
ing according to the WHO classification.29,30
Intravenous contrast-enhanced, cross-sectional imaging from the skull
base to the symphysis was required for staging. Investigation of the neck,
abdomen, and pelvis could be performed either by computed tomography
(CT) or magnetic resonance imaging, whereas a chest CT was mandatory. In
addition, abdominal ultrasonography had to be performed. All cross-sectional
images were real-time reviewed centrally by the tumor board of the study.
Bone marrow biopsy was recommended in patients with a clinical stage greater
than IIA. Suspected bone involvement was specifically imaged by bone scin-
tigraphy, CT bony window, magnetic resonance imaging, or conventional
radiographs of the respective site(s). Fluorodeoxyglucose positron emission
tomography scanning of the whole body was optional and could be subject to
central review.
Response assessment after two cycles had to be performed in all patients.
A late response assessment was scheduled for patients in TG-2 after four cycles
and for patients in TG-3 after six cycles of chemotherapy. Response assessment
imaging had to be performed according to the requirements for staging in all
initially involved regions. After review of the response assessment, the central
review board provided radiotherapy recommendations for all TG-2 and TG-3
patients, as well as for TG-1 patients who were not in complete remission.
The definition of disease stages was adopted according to the Ann Arbor
Conference classification. Patients were stratified into the following three TGs
according to disease stage: TG-1 (early stages: IA, IB, and IIA), TG-2 (interme-
diate stages: IE, IIB, IIAE, and IIIA), and TG-3 (advanced stages: IIBE, IIIAE,
IIIB, IVA, IVB, and IVE; Fig 1).
Nodal involvement of a lymph node was defined if the node was greater
than 2 cm in largest diameter. The node was not involved if it was ⱕ 1 cm in
largest diameter and was considered questionably involved if the largest diam-
eter was between 1 and 2 cm. Involvement decision was then based on all
further clinical evidence available. In the central review board, reference vol-
umes were calculated from all involved nodal regions. The volume (V) was
calculated with three dimensions (a, b, and c) of a node or conglomerate
approximating an ellipsoid as follows: volume ⫽ (a ⫻ b ⫻ c)/2.
The response to chemotherapy after two, four, or six cycles was defined
as complete remission if the volume reduction was ⱖ 95% and ⱕ 2 mL of the
initial volume. The response was defined as unconfirmed complete remission
if the volume reduction was ⱖ 75% or less than 2 mL, and partial remission
(PR) was defined as 50% volume reduction.
© 2010 by American Society of Clinical Oncology 3681
 Mauz-Körholz et al
GPOH-HD 2002 Boys
2 × OE*PA CR: no RT
TG 1
I A/B, II A
non CR: involved field
RT
TG 2 2 × OE*PA 2 × COPDAC
IEA/B, IIEA
II B, III A
Involved field RT
TG 3 2 × OE*PA 4 × COPDAC
IIEB, IIIEA/B
III B, IV A/B
1 5 9 13 17 21
Weeks
Fig 1. Study design of the German Society of Pediatric Oncology and Hematology–
Hodgkin’s Disease (GPOH-HD) 2002 study for male patients. Girls were similarly
treated with standard two cycles of vincristine, procarbazine, prednisone, and
doxorubicin instead of vincristine, etoposide, prednisone, and doxorubicin (OE*PA)
and cyclophosphamide, vincristine, procarbazine, and prednisone instead of cyclo-
phosphamide, vincristine, prednisone, and dacarbazine (COPDAC) in treatment
group (TG) 2⫹3. CR, complete remission; RT, radiotherapy.
All patients received two induction cycles, OPPA for girls and OE*PA for
boys. In addition, patients with intermediate- or advanced-stage disease re-
ceived two or four cycles, respectively, of COPP (girls) or COPDAC (boys).
OPPA cycles consisted of vincristine 1.5 mg/m2 IV on days 1, 8, and 15;
procarbazine 100 mg/m2 orally (PO) on days 1 to 15; prednisone 60 mg/m2 PO
on days 1 to 15; and doxorubicin 40 mg/m2 IV on days 1 and 15. OE*PA cycles
were identical to OPPA except that etoposide 125 mg/m2 IV on days 2 through
6 replaced procarbazine. COPP chemotherapy contained cyclophosphamide
500 mg/m2 IV on days 1 and 8; vincristine 1.5 mg/m2 IV on days 1 and 8;
procarbazine 100 mg/m2 PO on days 1 to 15, and prednisone 40 mg/m2 PO on
days 1 to 15. COPDAC cycles were identical to COPP except that dacarbazine
250 mg/m2 IV on days 1 to 3 replaced procarbazine (Fig 1). Chemotherapy-
related toxicity had to be graded and documented for each given cycle
according to National Cancer Institute Common Toxicity Criteria (NCI-
CTC; version 2.0).31
After chemotherapy, modified involved-field radiotherapy was delivered
to initially involved regions. Treated areas were smaller than classical involved
fields because upper and lower neck; supraclavicular region; upper, mid, and
lower mediastinal; and upper and lower para-aortic regions were distin-
guished. Lateral field borders for mediastinal or para-aortic regions were based
on tumor extension after chemotherapy. Standard recommended radiother-
apy dose was 19.8 Gy (1.8-Gy fractions). In regions with less than 75% volume
reduction, a boost to approximately 30 Gy was administered, and residual
masses greater than 100 mL were boosted to approximately 35 Gy. Stage IV
lung disease was irradiated only if lung nodules were still detectable after two
cycles of chemotherapy. Lung and liver radiation dose varied from 12 to 15 Gy
(1- to 1.2-Gy fractions). Radiotherapy was omitted in TG-1 patients in com-
plete remission after chemotherapy.
An interim analysis of the first 70 patients receiving COPDAC suggested
a trend toward 5-year EFS of less than 90%, although toxicity was low. There-
fore, the study committee decided to increase the dacarbazine dose from three
to four doses of 250 mg/m2. This amendment was activated August 3, 2005 and
was implemented in 20 boys only. Concomitantly, 12 trial sites started a
separate vinblastine, etoposide, cyclophosphamide, vincristine, prednisone,
and doxorubicin (VECOPA) pilot study recruiting nine TG-2⫹3 boys with
classical HL until the end of GPOH-HD-2002.
Statistical Methods
Here, we report on all patients with classical HL. Patients with LPHL have
been excluded for this report because LPHL is now generally considered a
separate disease entity,30 and some LPHL patients have been treated with
surgery only.32
3682 © 2010 by American Society of Clinical Oncology
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Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
Time to event data were analyzed using the Kaplan-Meier method33 and
the log-rank test.34 Overall survival was defined as time from registration until
death from any cause. Progression-free survival (PFS) was defined as time
from registration until the progression/relapse of disease or death from any
cause, whichever occurred first. EFS was defined as time from registration until
the occurrence of one of the following events: progression/relapse of disease,
occurrence of a secondary malignancy, or death from any cause. The cutoff for
data analysis was February 25, 2010.
GPOH-HD-2002 was originally planned as a 1-year feasibility study to
pilot for a full randomized study comparing COPP and COPDAC. Start of this
randomized study (European Network Group on Pediatric Hodgkin’s Lym-
phoma [EuroNet-PHL] -C1 opened in 2007) was delayed because of a delay in
funding and the foundation of a European study group (EuroNet-PHL). Thus,
GPOH-HD-2002 over-recruited into a full study generation.
RESULTS
Patient Characteristics
From November 2002 until December 2005, 660 consecutive
patients were enrolled onto the study. Thirty patients had to be ex-
cluded. The diagnosis was revised by reference pathology in five
patients, and five patients had comorbidities (immunodeficiency syn-
dromes, n ⫽ 2; cardiac diseases, n ⫽ 2; and secondary HL, n ⫽ 1). Ten
patients were older than age 18 years at diagnosis, eight patients were
referred for consultation only or from nonparticipating trial sites, and
two patients had prior chemotherapy. Furthermore, 57 patients with
LPHL were excluded from this analysis. The demographics and clini-
cal characteristics of 573 study patients with classical HL (287 boys and
286 girls; mean age, 14 years; range, 2.8 to 18 years) are listed in Table
1. Five hundred sixty-seven (99%) of 573 study patients had central
review of staging. In nine patients (1.4%), the TG was assigned by local
staging and differed from central review. Fifteen patients (2.6%) had
individual chemotherapy modifications. Analysis is based on the TG
as treated. The proportions of patients in TG-1, TG-2, and TG-3
were 34.0%, 24.3%, and 41.7%, respectively. Three hundred
seventy-eight patients (183 boys and 195 girls) were classified as
having intermediate- or advanced-stage disease (TG-2⫹3; Table 1).
Treatment Results and Toxicity
Median follow-up time was 58.6 months. Fifteen patients died,
and 10 deaths were related to HL progression or relapse. Two deaths
were toxic deaths (intracranial hemorrhage after lysis of sinus venous
thrombosis after the first OEPA cycle and allergic shock and renal
failure after the second COPDAC cycle). Three patients died of other
causes (one patient with relapse of ovarian carcinoma surgically re-
moved before HL, one girl with secondary myelodysplastic syndrome/
AML, and one suicide).
Second malignancies occurred in 10 girls; in three of these pa-
tients the tumors were considered unrelated to HL treatment (one
ovarian teratoma, one ovarian carcinoma, and one retrothyroidal
fibrosarcoma) because the tumors occurred during or soon after treat-
ment. The remaining seven tumors occurred after full therapy, includ-
ing radiotherapy (five thyroid carcinomas, one nasopharyngeal
carcinoma, and one secondary AML). In one boy, secondary T-cell
acute lymphocytic leukemia occurred. The median latency period for
a second malignancy was 48.1 months (range, 2.7 to 63.3 months).
Overall, the probability estimates of overall survival, PFS, and
EFS at 5 years were 97.4% ⫾ 0.7%, 90.7% ⫾ 1.2%, and 89.0% ⫾ 1.4%,
respectively (Fig 2). The probabilities of PFS and EFS in TG-1, TG-2,
JOURNAL OF CLINICAL ONCOLOGY
 Procarbazine-Free Treatment in Pediatric Hodgkin’s Lymphoma

Table 1. Demographics and Clinical Characteristics of Eligible Study Patients and OS, PFS, and EFS
5-Year OS 5-Year PFS 5-Year EFS
No. of No. of No. of PFS No. of EFS
Characteristic Patients % SE (%) Deaths % SE (%) Events % SE (%) Events
All patients 573 97.4 0.7 15 90.7 1.2 53 89 1.4 62
Age, years
⬍ 13 169 98.2 1.0 4 94.6 1.8 10 93.9 1.9 11
ⱖ 13 404 97.0 0.9 11 89.0 1.6 43 86.9 1.8 51
Sex
Male 287 97.2 1.0 7 90.2 1.8 27 90.2 1.8 28
Female 286 97.5 0.9 8 91.1 1.7 26 87.7 2.0 34
Stage
I 14 100.0 NA 0 100.0 NA 0 91.6 7.9 1
II 313 98.0 0.8 6 89.6 1.7 32 87.7 1.9 37
III 110 95.8 2.1 4 93.0 2.6 7 92.1 2.7 9
IV 136 97.0 1.5 5 90.4 2.5 14 89.5 3.7 15
Symptoms
“A” 355 99.4 0.4 2 92.3 1.4 27 91.6 1.5 30
“B” 218 93.9 1.8 13 88.0 2.3 26 84.6 2.6 32
TG
1 195 99.5 0.5 1 92.7 1.9 14 92.0 2.0 15
2 139 98.5 1.0 2 93.4 2.1 9 88.3 2.9 15
3 239 94.9 1.5 12 87.4 2.2 30 86.9 2.3 32
2⫹3 378 96.2 1.0 14 89.6 1.6 39 87.7 1.8 47
Males 183 96.2 1.6 6 90.2 2.3 17 90.2 2.3 18
Females 195 96.3 1.4 8 89.1 2.3 22 84.7 2.7 29
RTⴱ
TG-1 RT omitted 62 100.0 NA 0 93.2 3.3 4 93.2 3.3 4
TG-1 RT received 126 100.0 NA 0 92.8 2.3 9 91.7 2.5 10

Abbreviations: OS, overall survival; PFS, progression-free survival; EFS, event-free survival; NA, not applicable; TG, treatment group; RT, radiotherapy.
ⴱ
Excluding one early toxic death and six patients with missing RT documentation.

and TG-3 patients at 5 years were 92.7% ⫾ 1.9% and 92.0% ⫾ 2.0%,
93.4% ⫾ 2.1% and 88.3% ⫾ 2.9%, and 87.4% ⫾ 2.2% and 86.9% ⫾
2.3%, respectively (P ⫽ .066/P ⫽ .15). The PFS and EFS probabilities
in TG-2⫹3 patients were 89.6% ⫾ 1.6% and 87.7% ⫾ 1.8%, respec-
tively (Fig 3; Table 1). Five-year PFS and EFS rates did not differ
significantly between boys and girls (PFS: 90.2% ⫾ 1.8% and 91.1% ⫾
1.7%, respectively; P ⫽ .93; EFS: 90.2% ⫾ 1.8% and 87.7% ⫾ 2.0%,
respectively; P ⫽ .38; Table 1).
In 62 TG-1 patients (31.8% of all TG-1 patients), radiotherapy
was omitted after completion of chemotherapy because of excellent

1.0
Proportion Without Event

1.0
0.8
Proportion Without Event

0.8
0.6

N = 573 0.6
0.4

5-yr OS 97.4%, 15 deaths

0.4
0.2 Log-rank P = .15
5-yr PFS 90.7%, 53 events
5-yr EFS 89.0%, 62 events TG1 5-yr EFS 92.0%, 15/195 events
0.2
TG2 5-yr EFS 88.3%, 15/149 events
0 20 40 60 80 TG3 5-yr EFS 86.9%, 32/239 events

Time (months) 0 20 40 60 80

Fig 2. Overall survival (OS), progression-free survival (PFS), and event-free
survival (EFS) for all patients in the German Society of Pediatric Oncology and
Hematology–Hodgkin’s Disease 2002 study. Kaplan-Meier curves for OS, PFS,
and EFS are presented for all study patients (N ⫽ 573). Median observation time
was 58.6 months. Five-year rate estimates are provided. For OS, events include
only death; for PFS, events include death and progression/relapse; and for EFS,
events include death, progression/relapse, and second malignancies. The treat-
ment results were at or around the target rate of 90%.
Time (months)
Fig 3. Event-free survival (EFS) according to treatment groups (TGs). Kaplan-
Meier curves of EFS are presented for the following three stratification groups:
TG1 (early stages), TG2 (intermediate stages), and TG3 (advanced stages). Death,
relapse/progression, and secondary malignancy counted as events. Median
observation time was 58.6 months. Five-year rate estimates are provided. There
is only a statistically nonsignificant trend between the treatment groups.

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 Mauz-Körholz et al

response (58 of 62 patients). PFS and EFS rates in patients who did not
receive radiotherapy (both 93.2% ⫾ 3.3%) were similar (P ⫽ .88 and
P ⫽ .74, respectively) to those in patients who received radiotherapy
(92.8% ⫾ 2.3% and 91.7% ⫾ 2.5%, respectively). PFS and EFS rates in
prepubertal patients (⬍ 13 years old) tended to be more favorable
(P ⫽ .085 and P ⫽ .036, respectively) than in postpubertal patients
(⬎ 13 years old; Table 1). PFS and EFS rates in TG-2⫹3 patients did
not differ by sex or chemotherapy (90.2% ⫾ 2.3% and 90.2% ⫾ 2.3%,
respectively, for boys [OE*PA-COPDAC] and 89.1% ⫾ 2.2% and
84.7% ⫾ 2.7%, respectively, for girls [OPPA-COPP]; P ⫽ .49 and
P ⫽ .12, respectively; Figs 4A and 4B; Table 1).
In all chemotherapy blocks (OPPA/OE*PA and COPP/COPDAC
in TG-2 and TG-3), more than 90% of all patients received more than
90% of their target doses of all single drugs, except for vincristine in
COPP/COPDAC in TG-3, where only 89.4% of patients received
more than 90% of their target dose.
In the OE*PA regimen, hematotoxicity was the most common
recorded adverse reaction greater than NCI-CTC grade 2. Maximum
A 1.0
Proportion Without Event
NCI-CTC grade 3 or 4 leukopenia, neutropenia, anemia, and throm-
bocytopenia were recorded in 70.5%, 81.5%, 11.9%, and 2.8% of
patients receiving OE*PA compared with 52.4%, 57.1%, 9.9%, and
0.7% of patients receiving OPPA. Rates of leukopenia and neutrope-
nia with OE*PA were significantly higher compared with OPPA
(P ⬍ .001; Table 2). NCI-CTC grade 3 or 4 infections were infrequent,
and there were no early deaths as a result of infection.
In COPDAC cycles, NCI-CTC grade 3 or 4 hematotoxicity rates
were significantly lower compared with the COPP cycles. Leukopenia,
neutropenia, anemia, and thrombocytopenia were recorded in
13.1%, 22.7%, 6.9%, and 3.4% of patients, respectively, receiving
COPDAC. NCI-CTC grade 3 or 4 infections were rare (0.8% and 0%
with COPDAC and COPP, respectively). Interestingly, NCI-CTC
grade ⱖ 2 sensory and motor neurotoxicity rates were significantly
lower with COPDAC compared with those recorded for COPP
(2.3% v 7.0% and 1.7% v 10.0%, respectively; P ⬍ .005; Table 2).
Adherence to central review radiotherapy recommendations was
verified by documentation forms and physicians’ reports in 522 of 573
patients, excluding progression before end of radiotherapy (n ⫽
11) or toxic death (n ⫽ 1). Radiotherapy with 19.8 Gy was recom-
mended in 426 of 522 patients, no radiotherapy was recommended
in 62 of 522 patients, and boost radiotherapy was recommended in
34 of 522 patients. Treatment differed from these recommendations

0.8 in only 18 patients (3.4%).

0.6
DISCUSSION
0.4
Log-rank P = .49
TG2+3 5-yr PFS Boys/OEPA-COPDAC In 2002, the GPOH-HD study group changed the chemotherapy for
0.2 90.2%, 17/183 events
TG2+3 5-yr PFS Girls/OPPA-COPP
male pediatric patients with HL for two reasons. First, in DAL-HD-905
89.1%, 22/195 events and GPOH-HD-95,6 results for boys were slightly inferior to results
for girls. Therefore, we increased the dose of etoposide in OE*PA by
0 20 40 60 80
25%. Second, although fertility data in TG-1 had improved after the
Time (months) change from OPPA to OEPA in DAL-HD-90, elevated follicle-
B stimulating hormone levels in TG-2⫹3 patients suggested a persistent
1.0
fertility problem probably as a result of procarbazine in COPP. There-
Proportion Without Event

fore, procarbazine in COPP was replaced by dacarbazine, creating the

0.8
novel regimen COPDAC. Dacarbazine is an alkylator like procarba-
zine, has been extensively used in the ABVD regimen, and seems to be
0.6 less gonadotoxic. The overall treatment results in 573 patients with
classical HL confirm the good results of the preceding DAL-HD-90
0.4 and GPOH-HD-95 studies.
Log-rank P = .12
TG2+3 5-yr EFS Boys/OEPA-COPDAC In GPOH-HD-95, TG-1 patients achieving a complete remission
90.2%, 18/183 events
0.2 after OPPA or OEPA chemotherapy did not require radiotherapy.
TG2+3 5-yr EFS Girls/OPPA-COPP
84.7%, 29/195 events This applies to approximately 30% of the patients. GPOH-HD-2002
confirms this important result. Patients in TG-1 who did and did not
0 20 40 60 80
receive radiotherapy both had excellent results.
Time (months) The alternative chemotherapy OE*PA-COPDAC regimen for
boys is feasible even in a broad multicenter setting. More than 90% of
Fig 4. (A) Progression-free survival (PFS) and (B) event-free survival (EFS) by
the target dose was given to approximately 90% of the patients for all
sex/chemotherapy in treatment group (TG) 2⫹3. Kaplan-Meier curves of PFS and
EFS are presented for boys (treated with vincristine, etoposide, prednisone, and drugs administered. The hematotoxicity after OE*PA is more pro-
doxorubicin [OEPA]– cyclophosphamide, vincristine, prednisone, and dacarbazine nounced than with OPPA. However, COPDAC is less hematotoxic
[COPDAC]) and girls (treated with vincristine, procarbazine, prednisone, and doxoru-
bicin [OPPA]– cyclophosphamide, vincristine, procarbazine, and prednisone [COPP])
than COPP.
in TG2 (intermediate stages) and TG3 (advanced stages). Median observation time In intermediate- and advanced-stage disease (TG-2⫹3), PFS
was 58.6 months. Five-year rate estimates are provided. Death and relapse/ curves for girls treated with standard OPPA-COPP and boys treated
progression counted as events in PFS. Death, relapse/progression, and secondary
malignancy counted as events in EFS. There was no statistically significant differ- with OE*PA-COPDAC are superimposable. This holds true also
ence in PFS or EFS between sex or chemotherapy. when considering TG-2 and TG-3 separately (data not shown). The

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 Procarbazine-Free Treatment in Pediatric Hodgkin’s Lymphoma

Table 2. Toxicities of Chemotherapy Cycles in the GPOH-HD-2002 Study

Regimen (% of patients) Regimen (% of patients)

Grade 3 or OEPA OPPA COPDAC COPP

4 NCI-CTC (n ⫽ 561) (n ⫽ 573) P (n ⫽ 347) (n ⫽ 378) P
Anemia 11.9 9.9 NS 6.9 17.4% .003
Leukopenia 70.5 52.4 ⬍ .001 13.1 72.1% ⬍ .001
Neutropenia 81.5 57.1 ⬍ .001 22.7 58.6% ⬍ .001
Thrombocytopenia 2.8 0.7 .1 3.4 8.7% .04
Stomatitis 8.7 1.5 ⬍ .001 0 0 NA
Constipation 7.3 6.3 NS 1.7 3.5 NS
Neurotoxicity, sensory 1.3 0 NS 2.3 7.0 .04
Neurotoxicity, motor 1.4 1.8 NS 1.7 10.0 .001

Abbreviations: GPOH-HD, German Society of Pediatric Oncology and Hematology–Hodgkin’s Disease; NCI-CTC, National Cancer Institute Common Toxicity Criteria;
OEPA, vincristine, etoposide, prednisone, and doxorubicin; OPPA, vincristine, procarbazine, prednisone, and doxorubicin; COPDAC, cyclophosphamide, vincristine,
prednisone, and dacarbazine; COPP, cyclophosphamide, vincristine, procarbazine, and prednisone; NS, not significant; NA, not applicable.

present study constitutes no randomized comparison because treat-

ment was stratified by sex. However, the comparison is probably only
conservatively biased because results of boys tended to be slightly
inferior in previous studies. In addition, male sex is a known prognos-
tic factor in the adult International Prognostic Score.17 Thus, we
consider OE*PA-COPDAC a safe treatment alternative to OPPA-
COPP. Currently, a randomized study comparing OE*PA-COPP
with OE*PA-COPDAC with concomitant fertility testing (EuroNet-
PHL-C1)35 is ongoing.
Interestingly, second malignancies within the present study oc-
curred predominantly in girls (10 of 11 second malignancies), so our
conclusion is even stronger when looking at EFS. Five of 10 secondary
cancers in females were thyroid cancers, which have a female prepon-
derance in non– cancer survivors as well,36 and four of the five thyroid
cancers were microcarcinomas. Because diagnostic means for thyroid
carcinoma have rapidly improved over time, microcarcinomas may
have been missed in former studies.
Because fertility assessment was not an objective of GPOH-HD-
2002, fertility data were not prospectively collected. Although procar-
bazine is generally considered more gonadotoxic than dacarbazine,
Viviani et al22 reported on a relevant proportion of male patients being
diagnosed as already infertile before the start of HL treatment. Thus,
the hypothesis still requires proof of whether the elimination of pro-
carbazine leads to preservation of male fertility in intermediate- and
advanced-stage disease. This question is currently under investigation
in the prospective EuroNet-PHL-C1 trial.35 In conclusion, OPPA-
COPP and OE*PA-COPDAC seem to be exchangeable regimens in
intermediate- and advanced-stage HL in pediatric patients.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Christine Mauz-Körholz, Wolfgang Dörffel,
Dirk Hasenclever, Dieter Körholz
Administrative support: Alexander Fosså
Provision of study materials or patients: Christine Mauz-Körholz, Jonas
Karlén, Eva Bergsträsser, Alexander Fosså, Georg Mann, Michael
Hummel, Wolfram Klapper, Harald Stein, Regine Kluge, Dieter Körholz
Collection and assembly of data: Christine Mauz-Körholz, Tanja Pelz,
Antje Voigt, Martina Stiefel, Melanie Winkler, Constanze Vilser, Michael
Hummel, Harald Stein
Data analysis and interpretation: Christine Mauz-Körholz, Dirk
Hasenclever, Kathrin Ruschke, Dirk Vordermark, Regine Kluge,
Dieter Körholz
Manuscript writing: Christine Mauz-Körholz, Dirk Hasenclever,
Wolfgang Dörffel, Karin Dieckmann, Alexander Fosså, Dirk
Vordermark, Dieter Körholz
Final approval of manuscript: Christine Mauz-Körholz, Dirk
Hasenclever, Wolfgang Dörffel, Kathrin Ruschke, Tanja Pelz, Antje
Voigt, Martina Stiefel, Melanie Winkler, Constanze Vilser, Karin
Dieckmann, Jonas Karlén, Eva Bergsträsser, Alexander Fosså, Georg
Mann, Michael Hummel, Wolfram Klapper, Harald Stein, Dirk
Vordermark, Regine Kluge, Dieter Körholz

REFERENCES
1. Schellong G, Waubke-Landwehr AK, Langermann
HJ, et al: Prediction of splenic involvement in chil-
dren with Hodgkin’s lymphoma: Significance of
clinical and intraoperative findings—A retrospec-
tive statistical analysis of 154 patients in the German
therapy study DAL-HD-78. Cancer 57:2049-2056,
1986
2. Schellong G, Brämswig J, Ludwig R, et al:
Combined treatment strategy in over 200 children with
Hodgkin’s lymphoma: Graduated chemotherapy, in-
volved field irradiation with low dosage and selective
splenectomy—A report of the cooperative therapy
study DAL-HD-82. Klin Pädiatr 198:137-146, 1986
3. Schellong G, Hörnig I, Brämswig J, et al: Signif-
icance of procarbazine in the chemotherapy of
Hodgkin’s disease: A report of the Cooperative Ther-
apy Study DAL-HD-85. Klin Pädiatr 200:205-213, 1988
4. Schellong G, Hörnig-Franz I, Rath B, et al:
Reducing radiation dosage to 20-30 Gy in combined
chemo-/radiotherapy of Hodgkin’s lymphoma in
childhood: A report of the cooperative DAL-HD-87
therapy study. Klin Pädiatr 206:253-262, 1994
5. Schellong G, Pötter R, Brämswig J, et al: High
cure rates and reduced long-term toxicity in pediatric
Hodgkin’s lymphoma: The German-Austrian multi-
center trial DAL-HD-90 —The German-Austrian Pe-
diatric Hodgkin’s Disease Study Group. J Clin Oncol
17:3736-3744, 1999
6. Dörffel W, Lüders H, Rühl U, et al: Preliminary
results of the multicenter trial GPOH-HD 95 for the
treatment of Hodgkin’s lymphoma in children and
adolescents: Analysis and outlook. Klin Pädiatr 215:
139-145, 2003
7. Schellong G: Treatment of children and ado-
lescents with Hodgkin’s lymphoma: The experience
of the German-Austrian Paediatric Study Group.
Baillieres Clin Haematol 9:619-634, 1996
8. Schellong G, Riepenhausen M: Spätfolgen
nach Morbus Hodgkin bei Kindern und Jugendlichen.

www.jco.org © 2010 by American Society of Clinical Oncology 3685

Downloaded from jco.ascopubs.org on May 2, 2012. For personal use only. No other uses without permission.
Copyright © 2010 American Society of Clinical Oncology. All rights reserved.

Ergebnisse der Studien DAL-HD-78 bis -HD-90, 2002;
Projektbericht. Münster, Germany, Eigenverlag, 2002
9. Metzger ML, Hudson MM: Balancing efficacy and
safety in the treatment of adolescents with Hodgkin’s
lymphoma. J Clin Oncol 27:6071-6073, 2009
10. Hancock SL, Donaldson SS, Hoppe RT: Car-
diac disease following treatment of Hodgkin’s dis-
ease in children and adolescents. J Clin Oncol
11:1208-1215, 1993
11. Meadows AT, Obringer AC, Marrero O, et al:
Second malignant neoplasms following childhood
Hodgkin’s disease: Treatment and splenectomy as
risk factors. Med Pediatr Oncol 17:477-484, 1989
12. Schellong G, Riepenhausen M, Creutzig U, et
al: Low risk of secondary leukemias after chemother-
apy without mechlorethamine in childhood Hodgkin’s
disease: German-Austrian Pediatric Hodgkin’s Disease
Group. J Clin Oncol 15:2247-2253, 1997
13. Chabner BA, Longo DL (eds): Cancer Chemo-
therapy and Biotherapy: Principles and Practice.
Philadelphia, PA, Lippincott-Raven, 1996, p 32
14. Kreuser ED, Xiros N, Hetzel WD, et al: Repro-
ductive and endocrine gonadal capacity in patients
treated with COPP chemotherapy for Hodgkin’s
disease. J Cancer Res Clin Oncol 113:260-266, 1987
15. Brämswig JH, Heimes U, Heiermann E, et
al: The effects of different cumulative doses of
chemotherapy on testicular function: Results in 75
patients treated for Hodgkin’s disease during child-
hood or adolescence. Cancer 65:1298-1302, 1990
16. Gerres L, Brämswig JH, Schlegel W, et al: The
effects of etoposide on testicular function in boys
treated for Hodgkin’s disease. Cancer 83:2217-
2222, 1998
17. Hasenclever D, Diehl V: A prognostic score for
advanced Hodgkin’s disease: International Prognos-
tic Factors Project on Advanced Hodgkin’s Disease.
N Engl J Med 339:1506-1514, 1998
18. Kollmannsberger C, Beyer J, Droz JP, et al:
Secondary leukemia following high cumulative
3686 © 2010 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 2, 2012. For personal use only. No other uses without permission.
Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
Mauz-Körholz et al
doses of etoposide in patients treated for advanced
germ cell tumors. J Clin Oncol 16:3386-3391, 1998
19. Whitlock JA, Greer JP, Lukens JN:
Epipodophyllotoxin-related leukemia: Identification
of a new subset of secondary leukemia. Cancer
68:600-604, 1991
20. Winick NJ, McKenna RW, Shuster JJ, et al:
Secondary acute myeloid leukemia in children with
acute lymphoblastic leukemia treated with etopo-
side. J Clin Oncol 11:209-217, 1993
21. Viviani S, Santoro A, Ragni G, et al: Gonadal
toxicity after combination chemotherapy for Hodgkin’s
disease: Comparative results of MOPP vs ABVD. Eur J
Cancer Clin Oncol 21:601-605, 1985
22. Viviani S, Ragni G, Santoro A, et al: Testicular
dysfunction in Hodgkin’s disease before and after
treatment. Eur J Cancer 27:1389-1392, 1991
23. Frei E 3rd, Luce JK, Talley RW, et al: 5-(3,3-
dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-
45388) in the treatment of lymphoma. Cancer
Chemother Rep 56:667-670, 1972
24. Klener P, Donner L: Imidazole carboxamide
(DTIC) in the treatment of advanced lymphomas:
Efficacy of DTIC in cases which fail to respond to
conventional chemotherapeutic combinations. Acta
Haematol 57:272-278, 1977
25. Carter SK, Livingston RB: Single-agent ther-
apy for Hodgkin’s disease. Arch Intern Med 131:
377-387, 1973
26. Kaatsch P, Spix J: German Childhood Cancer
Registry: Annual report 2006/07 (1980-2006). Mainz,
Germany, Institute for Medical Statistics, Epidemi-
ology, and Informatics, University Mainz, 2008.
http://www.kinderkrebsregister.de
27. Steliarova-Foucher E, Kaatsch P, Lacour B, et
al: Quality, comparability and methods of analysis of
data on childhood cancer in Europe (1978-1997):
Report from the ACCIS project. Eur J Cancer 42:
1915-1951, 2006
■ ■ ■
28. Kaatsch P, Haaf G, Michaelis J: Childhood
malignancies in Germany: Methods and results of a
nationwide registry. Eur J Cancer 31A:993-999,
1995
29. Harris NL, Jaffe ES, Stein H, et al: A revised
European-American classification of lymphoid neo-
plasms: A proposal from the International Lym-
phoma Study Group. Blood 84:1361-1392, 1994
30. Harris NL, Jaffe ES, Diebold J, et al: World
Health Organization classification of neoplastic dis-
eases of the hematopoietic and lymphoid tissues:
Report of the Clinical Advisory Committee meeting—
Airlie House, Virginia, November 1997. J Clin Oncol
17:3835-3849, 1999
31. Trotti A, Byhardt R, Stetz J, et al: Common
toxicity criteria: Version 2.0 —An improved refer-
ence for grading the acute effects of cancer treat-
ment: Impact on radiotherapy. Int J Radiat Oncol
Biol Phys 47:13-47, 2000
32. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever
D, et al: Resection alone in 58 children with limited
stage, lymphocyte-predominant Hodgkin lympho-
ma: Experience from the European Network Group
on Pediatric Hodgkin Lymphoma. Cancer 110:179-
185, 2007
33. Kaplan EL, Meier P: Nonparametric estima-
tion from incomplete observations. J Am Stat Assoc
53:457-481, 1958
34. Peto R, Peto J: Asymptotically efficient rank
invariant test procedures. J R Stat Soc A 135:185-
207, 1972
35. Körholz D, Wallace WH, Landman-Parker J:
EuroNet-Paediatric Hodgkin’s Lymphoma Group
(EuroNet-PHL-C1): First international inter-group study for
classical Hodgkin’s lymphoma in children and adoles-
cents. http://clinicaltrials.gov/ct/show/NCT00433459
36. Hodgson NC, Button J, Solorzano CC: Thyroid
cancer: Is the incidence still increasing? Ann Surg
Oncol 11:1093-1097, 2004
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