Published Ahead of Print on August 24, 2015 as 10.1200/JCO.2014.59.
4853
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.4853
JOURNAL OF CLINICAL ONCOLOGY
Christine Mauz-Körholz and Dieter
Körholz, Martin-Luther-University Medi-
cal Center, Halle, Germany; Monika L.
Metzger, St Jude Children’s Research
Hospital, Memphis, TN; Kara M. Kelly,
Columbia University Medical Center,
New York, NY; Cindy L. Schwartz, MD
Anderson Cancer Center, Houston, TX;
Mauricio E. Castellanos, Unidad Nacio-
nal Oncologia Pediatrica, Guatemala
City, Guatemala; Karin Dieckmann,
Medical University of Vienna, Vienna,
Austria; and Regine Kluge, University of
Leipzig, Leipzig, Germany.
Published online ahead of print at
www.jco.org on August 24, 2015.
Both C.M.-K. and M.L.M. contributed
equally to this work.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Christine Mauz-
Körholz, MD, Universitätsklinik und
Poliklinik, für Kinder- und Jugendme-
dizin, der Martin-Luther-Universität
Halle-Wittenberg, Ernst-Grube-Straße
40, 06120 Halle (Saale), Germany;
e-mail: christine.mauz-koerholz
@uk-halle.de.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3399-1/$20.00
DOI: 10.1200/JCO.2014.59.4853
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Copyright © 2015 American
Copyright 2015 by American Society of Clinical Oncology
R E V I E W A R T I C L E
Pediatric Hodgkin Lymphoma
Christine Mauz-Körholz, Monika L. Metzger, Kara M. Kelly, Cindy L. Schwartz, Mauricio E. Castellanos,
Karin Dieckmann, Regine Kluge, and Dieter Körholz
A B S T R A C T
Hodgkin lymphoma (HL) is one of the most curable pediatric and adult cancers, with long-term
survival rates now exceeding 90% after treatment with chemotherapy alone or combined with
radiotherapy (RT). Of note, global collaboration in clinical trials within cooperative pediatric HL
study groups has resulted in continued progress; however, survivors of pediatric HL are at high risk
of potentially life-limiting second cancers and treatment-associated cardiovascular disease. Over
the last three decades, all major pediatric and several adult HL study groups have followed the
paradigm of response-based treatment adaptation and toxicity sparing through the reduction or
elimination of RT and tailoring of chemotherapy. High treatment efficacy is achieved using
dose-dense chemotherapy. Refinement and reduction of RT have been implemented on the basis
of results from collaborative group studies, such that radiation has been completely eliminated for
certain subgroups of patients. Because pediatric staging and response criteria are not uniform,
comparing the results of trial series among different pediatric and adult study groups remains
difficult; thus, initiatives to harmonize criteria are desperately needed. A dynamic harmonization
process is of utmost importance to standardize therapeutic risk stratification and response
definitions as well as improve the care of children with HL in resource-restricted environments.
J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
For more than 30 years, collaborations among
INTRODUCTION
cooperative groups globally have led to varied treat-
Since the late 1970s, pediatric Hodgkin lymphoma ment approaches for pediatric HL. North American
(HL) has been treated succesfully in cooperative and most European study groups4,13,15-24 have fa-
group trials.1-5 Initially, high-dose extended-field vored combined-modality treatment approaches,
radiation proved to be effective in adults with early- whereas Central and South American groups25-27
have initially pursued chemotherapy-only regimens
stage disease, whereas chemotherapy combinations
of mechlorethamine, vincristine, procarbazine, (Table 1). Since 2005, most European groups have
and prednisone as well as doxorubicin, bleomy- been working together under the umbrella of the
cin, vinblastine, and dacarbazine (ABVD) or European Network for Pediatric Hodgkin Lym-
combined-modality treatment were reserved for phoma (EuroNet-PHL). The Pediatric Oncology
advanced disease.6 These treatments were modi- Group and Children’s Cancer Group have merged
fied for children by reducing radiation dose and to form the Children’s Oncology Group (COG), and
field size and relying on chemotherapy across all the Asociación de Hemato-Oncología Pediátrica de
disease stages. With increasing concerns about Centro América (AHOPCA) and the Grupo Argen-
aging survivors of pediatric cancer,7-9 general tino de Tratamiento de la Leucemia Aguda (GATLA)
treatment approaches for the disease have changed. have also recently agreed to implement the same pro-
The use of alkylators has been reduced and the tocol with the prospect of more South American sites
number and composition of chemotherapy cycles to follow.
have been adapted to individual risk factors.2-4,10,11 There is an increasing need to harmonize the
Radiotherapy (RT) has been limited to involved staging and response criteria (eg, [18F]fluoro-deoxy-
fields and doses adapted to disease risk.1,4 The glucose [FDG] –positron emission tomography
concept of using early response to tailor therapy [PET] response definitions) for pediatric HL, be-
in dose-dense regimens has been refined.11 Pro- cause risk classifications and treatment group
carbazine has been gradually eliminated to reduce allocations differ substantially among cooperative
the risk of infertility, and etoposide and doxoru- groups—it is important to compare the treatment
bicin substituted to reduce the cumulative alky- philosophies for adult and pediatric HL. The inter-
lating agent dose.11-14 national collaboration in pediatric HL has gained an
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from 131.111.164.128
 Mauz-Körholz et al

Table 1. Collaborative Pediatric Hodgkin Lymphoma Groups

Group Radiotherapy RCT

North American collaborations
St Jude–Stanford–Dana Farber28,29,30,31,32
Pediatric Oncology Group (POG)2,11,33-35
Children’s Cancer Group (CCG)3,36,37
Children’s Oncology Group (COG)38,39
European collaborations
German Austrian Pediatric Oncology Hematology Society-Hodgkin Study
Group (DAL/GPOH-HD)4,14-16
German Pediatric Oncology Group (GPOH-HD)13,17,18
Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)19
Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)20
Société Française de Lutte contre les Cancers et Leucémies de l’Enfant
et de l’Adolescent (SFCE)21
United Kingdom Children’s Cancer and Leukaemia Group (CCLG)22-24
European Network for Pediatric Hodgkin Lymphoma (EuroNet-PHL)†40
Latin American collaborations
Asociación de Haemato-Oncología Pediátrica de Centro América
(AHOPCA)†25,26
Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA)27
RA: anatomic response; IFRT for all patients (all risk groups) in non-CR No
RA: metabolic response (gallium scan); IFRT for all patients in Yes
nonmetabolic CR; IFRT randomization for all patients in metabolic
CR after all chemotherapy
RA: anatomic response; IFRT for all patients in non-CR; IFRT Yes
randomization for all patients in CR at early response assessment
RA: anatomic response; IFRT for intermediate-risk patients in non-CR; Yes
IFRT randomization for intermediate-risk patients in CR at early
response assessment
Yes, IFRT for all patients, all risk groups No
RA: anatomic response; IFRT for all patients, all risk groups in non-CR No
No, chemotherapy-only regimen No
Yes, IFRT for all patients, all risk groups No
Yes, IFRT for all patients in the low- and intermediate-risk groups No
Yes, RT only for patients in clinical stage I and those with bulky No
disease; No, chemotherapy-only regimens
RA: metabolic (PET) response; IFRT only for patients (all risk groups) Yesⴱ
with early response–positive PET
RA: anatomic response; IFRT for low- and intermediate-risk patients in No
non-CR; No, chemotherapy-only regimen for high-risk patients
No, chemotherapy only regimen (randomized) for favorable-risk Yes
patients Yes, IFRT for high-risk patients

Abbreviations: CR, complete response; IFRT, involved-field radiotherapy; PET, positron emission tomography; RA, response adaptation; RCT, randomized
controlled trial.
ⴱ
Chemotherapy randomization.
†Participating countries in EuroNet-PHL: Austria, Belgium, Czech Republic, Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal,
Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, Australia, Israel, and New Zealand.
‡Participating countries in AHOPCA: Guatemala, El Salvador, Honduras, Nicaragua, Dominican Republic, and Costa Rica.

interactive forum with the Children, Adolescent and Young Adult HL
(CAYAHL) symposia, which are held every 3 years. Study groups from
Europe, the Americas, Asia, Australasia, Africa, and the Middle East
are using this platform to share their clinical experiences.27a,42-47 The
Staging Evaluation and Response Criteria Harmonization (SEARCH)
effort for CAYAHL was also initiated through this platform.48,49
Treatment for pediatric HL has focused on minimizing toxicity
and late effects and preserving high cure rates. In this review, we
discuss the collaborative clinical trials on pediatric HL and their strat-
egies to reduce or eliminate RT. We also review the standardization of
FDG-PET evaluation definitions, harmonization of treatment results
from various study groups, and new agents under investigation in
pediatric HL.
OBJECTIVES OF CONTEMPORARY COLLABORATIVE
CLINICAL TRIALS
Contemporary pediatric HL trials have aimed to eliminate the go-
nadotoxic alkylator procarbazine, introduce dose-dense chemother-
apy cycles, and evaluate response-based treatment adaptations (Table
2 and Appendix Table A1, online only). In low- and middle-income
countries, the choice of treatment approach is driven by factors differ-
ent from those seen in European and North American groups, but this
will possibly also provide insights into response adaptation.
Elimination of Procarbazine and Introduction of
Dose-Dense Chemotherapy Regimens
The Deutsche Arbeitsgemeinschaft für Leukämieforschung
(DAL) and the German Society of Pediatric Oncology and
Hematology–Hodgkin’s Disease (GPOH-HD) have made several at-
tempts to eliminate procarbazine from the vincristine, procarbazine,
prednisone, and doxorubicin (OPPA) and cyclophosphamide, vin-
cristine, procarbazine, prednisone (COPP) cycles to reduce the risk of
male infertility and preserve high cure rates. The pivotal DAL-90 trial
demonstrated that etoposide can successfully replace procarbazine in
the OPPA induction cycle, thereby reducing the risk of male infertility
in early-stage HL.4 In the GPOH-HD-2002 trial, a completely
procarbazine-free regimen was given to boys by replacing procarba-
zine with dacarbazine to create the novel regimen vincristine, etopo-
side, prednisone, and doxorubicin– cyclophosphamide, vincristine,
prednisone, and dacarbazine (OEPA-COPDAC). Outcomes of boys
treated with the OEPA-COPDAC regimen were comparable to those
of girls receiving the OPPA-COPP standard treatment (Table 2).13 In
the GPOH-HD-2002/VECOPA pilot trial, another dose-intensive
procarbazine-free regimen comprising vinblastine, etoposide, cyclo-
phosphamide, vincristine, prednisone, and doxorubicin was explored
in the intermediate- and high-risk male patient groups.14 In contrast
to these gender-stratified trials, the effect of OEPA-COPDAC versus
OEPA-COPP is currently being studied in the European Network for
Pediatric Hodgkin Lymphoma (EuroNet-PHL) –C1 trial (Appendix

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from 131.111.164.128
 Pediatric Hodgkin Lymphoma

Table 2. Summary of Recently Evaluated First-Line Treatment Trials in Pediatric Classical Hodgkin Lymphoma

Study Risk Design No. Chemotherapy Radiation Key Findings

Children’s Oncology Group (COG)
Trials
AHOD003138 Intermediate Randomized with early 1,369 RER: 4 ⫻ ABVE- RER/CR: ⫾ 21 Gy IF Early response
response–based PC RER ⬍ CR: 21 Gy assessment
therapy tailoring IF supported omitting RT
in RERs with CR and
2002-2009 305 SER: 4 ⫻ ABVE- SER: 21 Gy IF
augmenting
PC ⫾ 2 ⫻ DECA
chemotherapy in
SERs with PET-
positive disease.
German Pediatric Oncology
Hematology Hodgkin
Disease (GPOH-HD) Study
Group
GPOH-HD-200213 Low (TG1) Nonrandomized, 195 Girls: 2 ⫻ OPPA CR: none Radiation can safely be
2002-2005 gender-stratified, Boys: 2 ⫻ OEPA ⬍ CR: 19.8 Gy IF omitted in patients
response-based RT who achieve CR after
allocation two cycles of OPPA
or OEPA.
Intermediate Nonrandomized, 139 Girls: 2 ⫻ OPPA ⫹ 19.8 Gy IF OEPA-COPP and OEPA-
(TG2) gender stratified 2 ⫻ COPP COPDAC are
Boys: 2 ⫻ OEPA ⫹ equivalent regimens
2 ⫻ COPDAC in intermediate-risk
patients.
High (TG3) Nonrandomized, 239 Girls: 2 ⫻ OPPA ⫹ 19.8 Gy IF OEPA-COPP and OEPA-
gender stratified 2 ⫻ COPP COPDAC are
Boys: 2 ⫻ OEPA ⫹ equivalent regimens
2 ⫻ COPDAC in high-risk patients.
St Jude–Stanford–Dana Farber
Consortium
HOD9928 Low Nonrandomized, 88 4 ⫻ VAMP CR: none Patients with highly
2000-2009 response-based RT ⬍ CR: 25 Gy IF favorable features can
allocation safely be treated
without alkylators and
RT if they achieve CR
after two cycles of
VAMP.
AHOPCA consortium
LH 199926 Favorable Nonrandomized, 94 6 ⫻ COPP ⫾ 4 ⫻ None Patients with ⬍ CR after
response-based COPP/ABV two cycles of COPP
chemotherapy received additional
allocation four cycles of COPP/
ABV.
1999-2004 Unfavorable Nonrandomized, 118 8 ⫻ COPP/ABV None All patients received
chemotherapy eight cycles of
allocation COPP/ABV.

NOTE. All drug doses are displayed in cumulative doses per cycle.
Abbreviations: ABVE-PC, doxorubicin 50 mg/m2, bleomycin 15 IU/m2, vincristine 2.8 mg/m2, etoposide 375 mg/m2, prednisone 280 mg/m2, cyclophosph-
amide 800 mg/m2; AVPC, doxorubicin 50 mg/m2, vincristine 2.8 mg/m2, prednisone 280 mg/m2, cyclophosphamide 1,200 mg/m2; COPDAC: cyclophosph-
amide 1,000 mg/m2, vincristine 3.6 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; COPP, cyclophosphamide 1,000 mg/m2, vincristine 3.6 mg/m2,
prednisone 600 mg/m2, procarbazine 1,500 mg/m2; COPP/ABV, cyclophosphamide 600 mg/m2, vincristine 1.5 mg/m2, prednisone 560 mg/m2, procarbazine
700 mg/m2, doxorubicin 30 mg/m2, vinblastine 6 mg/m2, bleomycin 10 IU/m2 ; COPP (AHOPCA), cyclophosphamide 600 mg/m2, vincristine 1.5 mg/m2,
prednisone 560 mg/m2, procarbazine 1,400 mg/m2; CR, complete response; DECA, dexamethasone 20 mg/m2, etoposide 200 mg/m2, cisplatin 60 mg/m2,
cytarabine 6,000 mg/m2; IF, involved field; OEPA, vincristine 5.4 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; OPPA,
vincristine 4.5 mg/m2, prednisone 900 mg/m2, procarbazine 1,500 mg/m2, doxorubicin 160 mg/m2; PET, positron emission tomography; RER, rapid early
responder; RT, radiotherapy; SER, slow early responder; VAMP, vinblastine 12 mg/m2, doxorubicin 50 mg/m2, methotrexate 40 mg/m2, prednisone
560 mg/m2.

Table A1).40 In this trial, all patients receive OEPA, but patients in the
intermediate- and high-risk groups—treatment groups 2 and 3—are
randomly assigned to receive COPP or COPDAC to test whether
equivalent results can be achieved with a less gonadotoxic
procarbazine-free regimen.
Similarly, the Pediatric Oncology Group developed a dose-dense
procarbazine-free regimen comprising doxorubicin, bleomycin, vin-
cristine, and etoposide and prednisone and cyclophosphamide.11 In
the original P9425 and P9426 trials, patients were randomly assigned
to receive the topoisomerase inhibitor dexrazoxane as a cardiopulmo-
nary protectant during treatment.50 Early evaluation of dexrazoxane-
associated second malignant neoplasms suggested an increased risk
for secondary acute myeloid leukemia (sAML) or myelodysplastic
syndrome, with 6 of 8 patients in the dexrazoxane arm developing
AML/myelodysplastic syndrome and 2 patients developing solid tu-
mors. The 4-year cumulative incidence rate of any secondary malig-
nancy was 2.55% for patients in the dexrazoxane arm versus 0.85% for
those in the nondexrazoxane arm (P ⫽ .06). Subsequent COG trials
have therefore discouraged the use of dexrazoxane, and the risk of
sAML in the nondexrazoxane arm seems to be low. In the

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 Mauz-Körholz et al
GPOH-HD-2002 trial, none of the 287 boys receiving the etoposide-
containing regimen developed sAML, whereas 1 girl who did not
receive etoposide developed sAML.13 The Stanford V regimen ad-
opted by the St Jude–Stanford–Dana Farber consortium is a
combined-modality strategy originally developed by an adult study
group51 in which a 12-week, multiagent, non– cross-resistant dose-
dense regimen combined with involved-field RT (IFRT) was given to
patients with intermediate- and advanced-stage HL (Appendix Table
A1).52 Mature long-term data from Stanford V show a low risk of
sAML for patients administered this regimen, with none of the 256
patients observed for more than 5 years developing sAML.53 In this
regimen, low cumulative doses of alkylating agents also improve the
prospects of fertility.
Response Adaptation to Reduce or Eliminate RT
In HL trials on adults, RT remains an essential component of
treatment, especially for patients with early-stage disease who are
treated with ABVD chemotherapy. In contrast, pediatric HL study
groups balance the risk-benefit ratio differently. Although
combined-modality approaches usually provide high response
rates with event-free survival (EFS) rates of approximately 90%,
the risk of radiation-induced second cancers, cardiovascular dis-
ease, and thyroid dysfunction in survivors of pediatric HL increases
throughout their lifetime.8,9,54,55
The CCG trial C5942, one of the first pediatric trials aimed at
eliminating RT, randomly assigned patients who had achieved ana-
tomic complete response (CR) after completion of COPP/ABV hybrid
chemotherapy to either IFRT or no further therapy.36 The 10-year EFS
rate, but not the overall survival (OS) rate, was significantly lower
among those treated with chemotherapy alone.56 However, this trial
was compromised by the use of less intensive chemotherapy than is
used in most contemporary trials. Despite international collabora-
tions, randomized clinical trials to evaluate the added benefit of RT
remain challenging in pediatric HL because the limited number of
patients makes it difficult to achieve statistical power. Therefore, most
collaborative consortia are adopting a response-based RT delivery in
which patients with an early favorable response to chemotherapy are
chosen to undergo reduced RT or forgo it completely. The St Jude–
Stanford–Dana Farber consortium evaluated response-based radia-
tion in low-risk patients treated with vinblastine, doxorubicin,
methotrexate, and prednisone (VAMP) chemotherapy. RT was ad-
ministered only to patients who did not achieve an early, that is, after
two cycles of VAMP, anatomic and metabolic CR. The 5-year EFS
rates of patients treated with four cycles of VAMP chemotherapy alone
and four cycles of VAMP chemotherapy plus 25.5 Gy IFRT28 were
similar (Table 2).
In the GPOH-HD95 trial, RT was omitted in patients achieving
anatomic CR after OEPA-COPP chemotherapy. The 10-year
progression-free survival (PFS) rate for patients with intermediate-
and advanced-stage disease (69% and 83%, respectively) was signifi-
cantly lower for patients with a CR than for those who did not achieve
a CR and received IFRT. The PFS rates for patients with low-risk
disease that did and did not receive RT were similar.18 However, the
OS rates of patients in all treatment groups were excellent and similar.
Thus, assessment by anatomic response at completion of chemother-
apy might not be adequate to identify patients who can receive re-
duced RT without increasing the risk of relapse.
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Among more contemporary pediatric trials, moderately dose-
intensified chemotherapy regimens have facilitated RT reduction
strategies. Early response assessment after more intensive doxorubi-
cin, bleomycin, vincristine, and etoposide and prednisone and cyclo-
phosphamide chemotherapy in the COG AHOD0031 trial identified a
group of early responders for whom RT could be eliminated without
compromising long-term survival.38 This study enrolled 1,712 eligible
patients and is the only random assignment phase III trial to assess
treatment stratification on the basis of early response. The EFS rate of
rapid early responders with an anatomic response of more than 80%
after two cycles and a negative gallium 67 or FDG-PET scan at the end
of all chemotherapy did not improve with the addition of RT. Simi-
larly, preliminary results of the COG AHOD0431 trial for low-risk HL
seem to have identified a group of very early responders (negative PET
scan after one cycle) who may have an improved outcome without
adjuvant RT.57 It is therefore not surprising that response assessment
has evolved, and, currently, more value is placed on functional assess-
ment by PET scans.
Recently, EuroNet-PHL completed its first large cooperative trial
(EuroNet-PHL-C1) on the basis of the GPOH-HD chemotherapy
backbone (OEPA-COPP/COPDAC) in which more than 2,100 pa-
tients were recruited. IFRT was administered only to patients whose
PET scans were positive after two initial OEPA cycles. Preliminary
results suggest that this strategy is feasible to identify patients who can
have good long-term survival without RT.
Table 3 summarizes the most recent strategies used to reduce or
eliminate RT in pediatric and adult HL trials. Although in seminal
pediatric trials early response adaptation was a key feature in
combined-modality approaches for eliminating RT in all risk groups,
elimination of RT is the main objective only in adult patients with
advanced-stage HL. RT remains a standard treatment element in adult
patients with early- and intermediate-stage disease.58-60 Essentially,
more intensive chemotherapy might be required to balance the elim-
ination of RT. Table 4 presents strategies for the systematic reduction
of radiation dose and field size as well as for omitting RT in patients
with early-stage classical HL (cHL). The table highlights the develop-
ment of RT regimens over eight consecutive trials of the DAL/GPOH-
HD/EuroNet-PHL groups.
Rationale for Therapy Approach and Response
Adaptation in Low- and Middle-Income Countries
In many low- and middle-income countries, health care institu-
tions that lack reliable access to radiation facilities, trained personnel,
and diagnostic imaging modalities have traditionally preferred
chemotherapy-only approaches. Earlier chemotherapy-only trials
prescribed six to 12 cycles of mechlorethamine, vincristine, procarba-
zine, and prednisone61,62; hybrid therapies containing alkylating
agents, such as chlorambucil, vinblastine, procarbazine, and predni-
sone63; or alternating non– cross-resistant regimens, such as COPP/
ABVD,64,65 COPP/ABV hybrids,66,67 or their combinations without
alkylating chemotherapy agents.68 GATLA evaluated chemotherapy
alone versus combined-modality therapy prospectively for early-stage
disease (stages I and II). The addition of IFRT improved the disease-
free survival rates for patients with more than two involved nodal
areas, bulky peripheral (⬎ 5 cm) adenopathy, bulky mediastinal ade-
nopathy, or advanced-stage disease.69 The next GATLA trial found
similar EFS rates for patients with favorable prognosis who were
randomly assigned to three or six cycles of chemotherapy; the results
JOURNAL OF CLINICAL ONCOLOGY
 Pediatric Hodgkin Lymphoma

Table 3. Summary of Recent Radiotherapy Reduction or Elimination Strategies in Pediatric and Adult Hodgkin Lymphoma Study Groups
St Jude–Stanford–Dana
Risk Group AHOPCA COG EuroNet-PHL C2-Trial Farber Consortium EORTC GHSG
Low CR after 4 ⫻ CR after cycle 3: AR at ERA: none CR: none ⬍ DV3 after 2 ⫻ All: 30 Gy INRT
ABVD: none none ABVD: none
⬍ CR after ⬍ CR: IFRT 21 IR at ERA (ⱖ DV4): ⬍ CR: 25 Gy TFRT ⱖ DV3 after 2 ⫻
4 ⫻ ABVD: 20 Gy mIFRT 19.8 Gy ABVD: 30 Gy
Gy IFRT INRT
Intermediate CR after 6 ⫻ RER after cycle 2, AR at ERA: none CR: 15 Gy IFRT All: 30 Gy INRT All: 30 Gy INRT
ABVD: none CR after cycle
4: none
⬍ CR after RER after cycle IR at ERA (ⱖ DV4): ⬍ CR: 25 Gy IFRT
6 ⫻ ABVD: 20 2, ⬍ CR after randomized:
Gy IFRT cycle 4: 21 Gy standard cht: mIFRT
IF 19.8 Gy ⫹ 10 Gy
SER after cycle 2: boost to LRA ⱖ
21 Gy IF DV3-positive sites;
intensified cht: 30
Gy to LRA ⱖ DV3-
positive sites only
High CR after 2 ⫻ RER: sites of AR at ERA: none CR after 2 ⫻ AEPA: Like GHSG 30 Gy INRT to LRA (ⱖ DV3)-
OEPA 4 ⫻ initial bulk none positive sites only, no
COPDAC: 20 21Gy irradiation of extranodal
Gy IFRT sites
⬍ CR after SER: PET-positive IR at ERA (ⱖ DV4): ⬍ CR after cycle 2 ⫻
2 ⫻ OEPA 4 ⫻ sites and/or randomized: AEPA: 25 Gy TFRT
COPDAC: 25 any site ⱖ 2.5 standard cht: mIFRT
Gy IFRT cm after cycle 2 19.8 Gy ⫹ 10 Gy
boost to LRA ⱖ
DV3-positive sites;
intensified cht: 30
Gy to LRA ⱖ DV3-
positive sites only

Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AEPA, Adcetris (brentuximab vedotin), prednisone, etoposide, doxorubicin; mIFRT, modified
involved-field radiotherapy; AHOPCA, Central American Association for Pediatric Hematology/Oncology; AR, adequate response after two cycles of initial OEPA
chemotherapy (ie, PET negative [⬍ DV4; ie, DV1-3]) and at least 50% volume reduction in bulk site; cht, chemotherapy; COG, Children’s Oncology Group; COPDAC,
cyclophosphamide, vincristine, prednisone, dacarbazine; CR, complete remission; DV, Deauville score for PET response assessment;74 EORTC, European
Organisation for Research and Treatment of Cancer; ERA, early response assessment after two cycles of initial OEPA chemotherapy; EuroNet-PHL, European
Network for Pediatric Hodgkin Lymphoma; GHSG, German Hodgkin Study Group; IFRT, involved-field radiotherapy; INRT, involved-node radiotherapy; IR, inadequate
response after two cycles of initial OEPA chemotherapy (ie, PET-positive ⱖ DV4 or ⬍ 50% volume reduction in bulk site; LRA, late response assessment after all
chemotherapy; OEPA, vincristine, prednisone, etoposide, doxorubicin; PET, positron emission tomography; RER, rapid early responder; SER, slow early responder;
TFRT, tailored-field radiotherapy.

of the chemotherapy-only approach were not different from the
combined-modality strategy of their previous trial.70
The Central American study group AHOPCA reported a 5-year
EFS of 61% with COPP with or without ABV and without RT across
all stages. Abandonment of therapy was the major factor affecting the
EFS rate, and substantial myelosuppression, especially for high-risk
patients, made this regimen difficult to administer (Table 2).26 In an
effort to reduce abandonment of therapy, AHOPCA switched to a
modified Stanford V regimen in 2004. Because preliminary results
suggested no improvement in EFS rates, in 2009, AHOPCA moved to
OEPA-COPDAC chemotherapy for this patient group (Appendix
Table A1).43,71 AHOPCA, GATLA, and other South American insti-
tutions are now sharing the same protocol, which uses ABVD for
low- and intermediate-risk patients and OEPA-COPDAC for
advanced-stage HL. A response-adapted approach is used to prescribe
RT. Given that the protocol is shared in Central and South America,
but PET-CT (computed tomography) is only available in some of the
South American sites, we will be able to compare the impact of an
anatomic response assessment versus a combined anatomic and func-
tional response assessment on the number of patients ultimately re-
ceiving RT and the EFS rates of the respective approaches. Because
prevention of abandonment and treatment-related deaths are other
major challenges in low- and middle-income countries, the CAYAHL
platform facilitates problem solving and improving the survival
of patients.
STANDARDIZING THE DEFINITIONS FOR FDG-PET EVALUATION
FDG-PET images are currently interpreted visually, which is subject to
high interobserver variability,72 and should therefore be centrally re-
viewed within a clinical trial for quality assurance. The five-point
Deauville score, currently the widely used evaluation standard,73 re-
lates the liver and mediastinum FDG uptake to the residual tumor
uptake at an early response time point. The specific Deauville cutoff
that defines adequate or inadequate response depends on the time of
assessment and intensity of the chemotherapy regimen. Therefore, the
complete metabolic FDG-PET response for assessment of early re-
sponse in trials using intensive treatment regimens is now defined as
Deauville 1 to 3.74,75 For assessment of late response, Deauville scores
of 3 or higher are considered FDG-PET positive, because this thresh-
old may indicate residual tumor after chemotherapy. This strategy has
successfully been applied in the German Hodgkin Study Group HD15
trial.76 The definition of FDG-PET positivity by the older Interna-
tional Harmonization Project score, using the mediastinal blood pool
and residual node size for reference, corresponds to a Deauville score
of less than 3.77

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 Mauz-Körholz et al

Table 4. Systematic Radiotherapy Reduction and Elimination Strategies in the DAL/GPOH-HD/EuroNet-PHL Trials
Standard Dose (Gy) and Field
Patients EFS, %
Trial (No.) RT Indication TG1 TG2 TG3 (years) OS (years)
DAL-HD 78 170 All patients 36-40 EF 36-40 EF 36-40 EF 89% (4) 91% (5)
1978-1981
DAL-HD 82 203 All patients 35 IF 30 IF 30 IF 96% (3) 95% (5)
1982-1984 5ⴱ 5ⴱ
DAL-HD 85 98 All patients 35 IF 30 IF 30 IF 74% (2) 98% (5)
1985-1986 5ⴱ 5ⴱ
DAL-HD 87 196 All patients 35 IF 25 IF 30 IF 85% (7) 97% (7)
1987-1990 5-10ⴱ 5ⴱ
DAL-HD 90 574 All patients 30 IF 25 IF 20 IF 90% (5) 98% (5)
1990-1995 5ⴱ 5-10ⴱ 10-15ⴱ
GPOH-HD 95 925 All patients not in CR at end of 20 mIF† 20 mIF 20 mIF 85% (10) 96% (10)
1995-2001 chemotherapy 10-15ⴱ 10-15ⴱ 10-15ⴱ
GPOH-HD 2002 573 All patients except TG1 in CR 20 mIF 20 mIF 20 mIF 89% (5) 97% (5)
2002-2005 10-15ⴱ 10-15ⴱ 10-15ⴱ
EuroNet-PHL-C1 2110 Only patients with PET Deauville score 20 mIF 20 mIF 20 mIF Not yet Not yet
2007-2013 ⱖ 3 after cycle 2 ⫻ OEPA 10ⴱ 10ⴱ 10ⴱ evaluated evaluated

Abbreviations: CR, complete remission (ⱖ 95% reduction of initial nodal volume and ⱕ 2 mL residual volume in any initially involved nodal site); EF, extended field;
EFS, event-free survival; IF, involved field; mIF, modified involved field; OS, overall survival; PET, positron emission tomography; RT, radiotherapy; TG1, treatment
group 1 (stages IA, IB, IIA); TG2, treatment group 2 (stages IAE, IBE, IIAE, IIB, IIIA); TG3, treatment group 3 (stages IIBE, IIIB, IVA, IVAE, IVB, IVBE).
ⴱ
Boost: If ⬍ 75% volume reduction or ⬎ 50 mL (DAL-HD90, GPOH-HD95) or ⬎ 100 mL (GPOH-HD 2002, EuroNet-PHL-C1) residual mass in any initially involved
nodal site.
†Modified involved field: Lateral margins of radiation fields depend on residual tumor extension after all chemotherapy.

In 2014, Hasenclever et al78 reported the quantitative PET evalu-

ation methodology to quantify the Deauville score. This method pro-
vides a semiautomatic quantification for early FDG-PET response in
HL and extends the ordinal Deauville scores to a continuous scale.
Deauville categories correspond to certain qPET values. Thresholds
between normal and abnormal response can be derived from the
distribution of qPET values in a patient cohort. In the EuroNet-
PHL-C1 trial, a certain qPET value after two cycles of OEPA chemo-
therapy helped differentiate an abnormal response with high
sensitivity. Total tumor glycolytic or metabolic volume methods are
also being investigated in pediatric HL.79
FDG-PET– guided response adaptation is being increasingly
used in pediatric HL. Figure 1 exemplifies how the concepts of re-
sponse evaluation may be interpreted differently by different study
groups, thereby affecting further therapy modifications. For the cur-
rent EuroNet-PHL-C2 trial, the definitions for PET response will be
changed to a higher threshold for PET positivity (Deauville 4) with the
aim of increasing the percentage of patients in whom RT can be
eliminated more than 50%. Accordingly, the patient shown in Figure
1 will not receive RT in the future.
Chemotherapy intensification will be one tool used to compen-
sate for the elimination for RT. In the COG AHOD0031 trial, the
chemotherapy response for the patient shown in Figure 1 would have
been interpreted as non-CR (ie, ⬍ 80% reduction) by two-
dimensional anatomic response assessment, which would have also
prompted IFRT after completing chemotherapy. The PET findings
after two cycles of chemotherapy were visually assessed and docu-
mented, but in contrast to the EuroNet-PHL-C1 trial, they were not
used to make further treatment decisions. The comparability of defi-
nitions for PET response and the varied use of CT criteria across
cooperative trial groups remains an important source of controversy.
IMPROVING THE COMPARABILITY OF CLINICAL TRIAL RESULTS
To accurately compare the results of different trials, it is essential to
confirm that equivalent criteria are used for staging, treatment alloca-
tion, and response assessment. Patients with HL are staged according
to the Ann Arbor classification with or without the Cotswolds modi-
fication.80 These criteria were defined in the 1960s and were based on
clinical, surgical, and two-dimensional imaging modalities, whereas
modern staging systems rely exclusively on anatomic cross-sectional
imaging (CT-MRI [magnetic resonance imaging]), mostly in combi-
nation with functional scans (PET-CT or PET-MRI). This may result
in a trend toward allocating patients to higher disease stages and
consequently higher risk groups because of more refined imaging
technologies and lead to overtreatment of some patients. However,
risk stratification and treatment group allocation differ widely not
only between adult and pediatric cooperative group trials but also
among the major pediatric HL study groups, and sometimes even
within the same group between generations of trials (Figure 2). Most
study groups perform quality assurance through a central multidisci-
plinary reference board for oncology, radiology, nuclear medicine
imaging, and RT within their trial series. Quality assurance offered
through central reference and consultation centers can improve PFS
rates by 10%.81 The Pediatric Hodgkin Network, a Web-based image
data exchange tool, has been established for quality assurance in the
EuroNet-PHL trials for European and extra-European countries.82,83
The SEARCH Effort for CAYAHL began in Arlington, Virginia,
in 2011, and continued in Cologne in 2013 and Berlin in 2014. First
results on issues related to staging harmonization were presented in
May 2014 during the Second International Symposium on CAYAHL
(2-ISCAYAHL 2014) in Berlin.48,49 Leaders of major pediatric HL
consortia from both sides of the Atlantic spearhead this ongoing effort.

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 Pediatric Hodgkin Lymphoma
A results among study groups and a more meaningful interpretation of
B required radiation.41 For nLPHL patients with incomplete resection,
Fig 1. (A) Fused [18F]fluoro-deoxy-glucose (FDG) positron emission tomog-
raphy (PET) computed tomography images and (B) nonfused PET images of
corresponding coronal (upper panels) and transversal (lower panels) slices at
initial diagnosis (left) and at response assessment after two cycles of
intensive chemotherapy (right) for a 15-year-old patient with classical Hodgkin
lymphoma. The blue arrows in the right panels indicate a small residual mass
with slightly enhanced FDG uptake after two cycles of chemotherapy. The
visual PET assessment was performed by five independent and specialized
nuclear medicine physicians. Deauville (DV) criteria assessment varied from
DV2 to DV4. Three experts assessed PET positivity as DV3, which was
considered positive during the European Network for Pediatric Hodgkin
Lymphoma Group trial C1 and was the basis for involved-field radiotherapy
administration. In addition, the patient received a radiation boost to the
residual mediastinal mass, which showed an anatomic volume reduction of
less than 75%. The semiautomatic quantification of the residual PET signal
resulted in a quantified PET value of 1.26, which also corresponded to DV3.78
PET images courtesy of Lorraine Wilson, MD, consultant in nuclear medicine,
Blackrock Clinic, Dublin, Ireland.
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The harmonization process aims at higher comparability of treatment
prognostic factors, but it may require continuous updating. Harmo-
nization is an ever-dynamic process, but it is indispensable for intro-
ducing new drugs and novel therapies in global trials.
EVALUATING TREATMENT FOR RARE OR
UNIQUE HISTOPATHOLOGIES
The recognition of nodular lymphocyte-predominant HL (nLPHL) as
a distinct entity by the WHO84 has generated interest in testing differ-
ent treatment approaches for cHL and nLPHL. Children with nLPHL
have an OS of approximately 100%, and nLPHL is frequently found as
a localized, early-stage disease. A meta-analysis of French, United
Kingdom, and German trial series showed that surgery alone was a
feasible option for localized disease, and yielded a long-term relapse-
free survival of 67%.85 COG AHOD03P1 prospectively evaluated 52
pediatric patients with stage I single-node disease treated with surgery
alone. Twelve patients who had stage IA relapse went on to receive
chemotherapy and had a 3-year OS of 100%; none of the patients
anthracycline-free chemotherapy combinations may be more effica-
cious than RT-only approaches, such as those used in adult patients.86
In a retrospective case series, Shankar et al87 reported a 3-year freedom
from treatment failure of 74% and OS of 100% for patients receiving
cyclophosphamide, vinblastine, and prednisone chemotherapy. Only
patients who did not at least achieve an unconfirmed CR (CRu;
ⱕ 25% of the initial diagnostic nodal volume and ⱕ 2 mL) were
treated with more intensive chemotherapy. In the prospective
AHOD03P1 trial, 137 low-risk patients receiving three cycles of doxo-
rubicin, vincristine, prednisone, and cyclophosphamide had a 4-year
EFS of 88% and a 4-year OS of 100%. Only 11 patients did not achieve
CR with this chemotherapy combination and required IFRT.41 In a
large retrospective report on 394 adult patients with nLPHL treated on
cHL studies with a combination of chemotherapy and RT regimens,
the relapse rate was not different between nLPHL and cHL patients.88
In contrast, the entity gray zone lymphoma (GZL), as defined by
the WHO,89 is a disease with intriguing features but lacking standard
treatment approaches. The features of GZL are intermediate between
those of cHL and diffuse large B-cell lymphoma or primary mediasti-
nal B-cell lymphoma or between nLPHL and T-cell–rich B-cell lym-
phoma or other variants. In a retrospective analysis, distinct histologic
patterns of nLPHL in adults have been correlated to prognostic fac-
tors.90 GZL, a rare entity, has been successfully treated either according
to protocols for cHL or mature B-cell non–Hodgkin lymphoma, de-
pending on whether the diagnosis was made at initial presentation or
at the time of relapsed or progressive disease. A preliminary anal-
ysis of the German HL and N-HL registries42 revealed that pediat-
ric patients with GZL were treated with either standard HL
regimens, such as OEPA-COPDAC with or without RT, or accord-
ing to intensive regimens for primary mediastinal B-cell
lymphoma, such as dose-adjusted etoposide, prednisone, cyclo-
phosphamide, and doxorubicin plus rituximab.91 For successfully
treating such rare entities, establishing a proper histopathologic
diagnosis, including confirmation by expert pathology review, is of
© 2015 by American Society of Clinical Oncology 7
 Mauz-Körholz et al

Study Group Risk IA IB IIA IIB IIIA IIIB IVA IVB

AHOD0431 – Low

COG E E
AHOD0031 – Intermediate
X X

AHOD0831 – High

TG1– Low

EuroNet-PHL-C1* E E E
TG2 – Intermediate
RF RF RF

TG3 – High E E

TL1 – Low

EuroNet-PHL-C2 E E E
TL2 – Intermediate
RF RF RF

TL3 – High E E

HOD99/HOD08 – Low < 3 ns

Pediatric Hodgkin Consortium E E

HOD05 – Intermediate
mX mX

HOD99/HLHR13 – High

Fig 2. Variation in risk stratification across pediartic Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral ⬎ 6 cm and mediastinal
bulk); mX, mediastinal bulk (ⱖ 0.33 mediastinal to thoracic ratio); ns, nodal site; TG, treatment group; TL, treatment level; RF, risk factors: erythrocyte sedimentation
rate ⱖ 30 mm/hour and/or bulk ⱖ 200 mL. (*) EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with ESR ⱖ 30 mm/hour and/or bulk ⱖ 200 mL were
treated in TG2 (intermediate risk).

utmost importance. Combined efforts for harmonization of diag-
nostic criteria across pediatric lymphoma study groups are re-
quired to facilitate global trials on these rare entities.
NEW AGENTS
In the last decade, efforts have focused on studying new drugs and
compounds targeting epitopes or signaling pathways of the Hodgkin
and Reed/Sternberg cells or the tumor microenvironment in relapsed
or refractory patients. Targeting the B-cell receptor– dependent nu-
clear factor-␬B pathway with compounds such as bortezomib, a pro-
teasome inhibitor that has favorable effects in vitro, has not proven
effective in phase I and II trials.92,93 A pediatric trial is currently
evaluating panobinostat, a histone deacetylase inhibitor, in patients
with relapsed HL, although this agent is likely more active when used
in combination with other agents.94
CD30, a member of the tumor necrosis factor-␣ receptor family,
which is expressed almost exclusively on HL cells, has been an attrac-
tive target for antibody therapy. Initial attempts of treatment with
naked CD30 antibodies were unsuccessful but later improved when
the antibody was coupled with radioactive compounds or cytotoxic
drugs. Patients with relapsed and refractory HL administered bren-
tuximab vedotin, an antibody– drug conjugate with the antitubulin
agent monomethyl auristatin E, had favorable overall response
rates.95,96 Long-term results have shown that brentuximab vedotin
monotherapy as second- or third-line treatment has not proven cura-
tive in patients with multiple relapses; the results of trials with this
compound in combination with conventional chemotherapy regi-
mens are not yet available. According to the principle of a most
effective first hit strategy, brentuximab vedotin has now been intro-
duced into first-line treatment in adults97 and children with HL. In an
ongoing study of the St Jude–Stanford–Dana Farber consortium,
brentuximab vedotin has replaced vincristine in the OEPA-COPDAC
regimen for high-risk patients98 with the aim of further reducing the
number of high-risk patients who require RT. With the same aim, the
COG is initiating a random assignment phase III trial to evaluate
the efficacy of brentuximab vedotin in combination with AVE-PC
chemotherapy.99 This is part of the overall treatment strategy for
pediatric HL to identify highly effective chemotherapy regimens that
minimize late effects and reduce the need for RT for the majority
of patients.
Nivolumab is another new agent currently under investigation
that seems to be highly efficacious in relapsed and refractory patients
with HL. This antibody may block the programmed death-1 pathway
thought to be used by Hodgkin and Reed/Sternberg cells to evade
immune detection. Early results are encouraging and suggest that
nivolumab has an exceptionally safe profile,100 thereby making it an
attractive candidate for early evaluation in pediatric patients.
FUTURE DIRECTIONS AND CONCLUSIONS
Increasing our knowledge about the genetic risk factors associated
with long-term sequelae can lead to the development of treatment
strategies that consider the individual’s genetic risk. Recently, Ma
et al101 showed that genetic polymorphisms of FGFR2 correlate

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from 131.111.164.128
 Pediatric Hodgkin Lymphoma

significantly with the risk of breast cancer after mediastinal irradi-
ation. In addition, estrogens may induce oncogenic effects through
FGFR2 signaling.102 Furthermore, decreased basic expression of
PRDM1, a tumor suppression gene, is significantly associated
with radiation-induced secondary cancer after childhood HL.103
Radiation-induced repression of the proproliferative gene Myc in
vitro is enhanced by high expression of PRDM1. Visscher et al104
recently showed that variants of the human concentrative nucleo-
side transporter SLC28A1 as well as the cassette transporter genes
ABCB4 or ABCC1 are significantly associated with an increased
risk of anthracycline-induced cardiotoxicity.
In the future, HL patients at high risk for anthracycline-induced
cardiotoxicity may be treated with combined-modality strategies that
limit anthracyclines, whereas patients at high risk for RT-induced
second malignancies may benefit more from intensive chemotherapy
regimens that spare RT. Multinational research programs that can
correlate cumulative long-term risk factors with genetic polymor-
phisms are required to investigate the feasibility and benefits of genet-
ically stratified therapy.
Between the end of the 1970s and the early 1990s, combined-
modality treatment approaches using chemotherapy with fairly low
cumulative doses of anthracyclines and RT yielded high cure rates in
children and adolescents with HL.1,28,29,105,106 Since then, the indica-
tion for a stepwise reduction of RT has been evaluated by using a
risk-stratified, response-adapted strategy according to anatomic and
metabolic response criteria. Thus, regimens with quite intensive but
toxic drug doses can compensate for RT and lead to excellent EFS
rates, but they may result in lower long-term OS rates as demonstrated
in a trial series on adults.107 Future efforts in the treatment of both
adults and children with HL should focus on developing personalized
therapies, considering individual risk factors, and introducing new
drugs with a safe profile that target specific HL pathways.
The progress and, consequently, the success in the treatment of
pediatric HL have largely been achieved through collaborative efforts
of national and multinational study groups. The ultimate goal for
collaborative efforts has always been the reduction of treatment bur-
den and the maintaining of high cure rates. In the future, novel
therapies and targeted compounds should be studied thoroughly in
ongoing collaborations to develop the most effective but even less
toxic treatments. Because HL affects young people in the prime of
their lives, it is important to efficiently control it. The effect of late
toxicities of these treatments needs to be limited, as they have a signif-
icant effect on society as a whole.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Christine Mauz- Körholz, Monika L. Metzger,
Kara M. Kelly, Cindy L. Schwartz, Dieter Körholz
Administrative support: Dieter Körholz
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors

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© 2015 by American Society of Clinical Oncology 11
 Mauz-Körholz et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Pediatric Hodgkin Lymphoma

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Christine Mauz-Körholz Mauricio E. Castellanos
No relationship to disclose No relationship to disclose
Monika L. Metzger Karin Dieckmann
No relationship to disclose No relationship to disclose
Kara M. Kelly Regine Kluge
No relationship to disclose No relationship to disclose
Cindy L. Schwartz Dieter Körholz
No relationship to disclose No relationship to disclose

© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Copyright © 2015 American Society
1, 2015 of Clinical Oncology. All rights reserved.
from 131.111.164.128
 Pediatric Hodgkin Lymphoma

Appendix

Table A1. Summary of Recently Completed but Not Yet Evaluated, Ongoing, and Future First-Line Treatment Trials in Pediatric Classical
Hodgkin Lymphoma
Study Risk Design Chemotherapyⴱ Radiation Comments
Children’s Oncology Group
(COG) trials
AHOD0431 Low Non randomized, 3 ⫻ AVPC CR: none Study completed, results
response-based RT ⬍ CR: 21 Gy IF under evaluation and
allocation suggest that CR status
after three cycles may
not optimally identify
patients in whom RT
can be omitted. Early
PET response (after one
cycle) appears to have
significant prognostic
implications
AHOD0831 High Non randomized, RER: 4 ⫻ ABVE-PC RER: sites of initial Study completed, results
response-based therapy SER: 2 ⫻ ABVE- bulk 21 Gy SER: under evaluation
allocation PC ⫹ 2 ⫻ IV ⫹ 2 PET-positive
ABVE-PC sites, any site
ⱖ 2.5 cm
AHOD1331 High Randomized chemotherapy Standard: 5 ⫻ bulky mediastinal Randomized chemotherapy
allocation with ABVE-PC mass, PET-avid allocation with
response-based RT Experimental: lesions after response-based RT
5 ⫻ Bv-AVE-PC cycle 2, 21 Gy
ISRT
European Network for
Pediatric Hodgkin
Lymphoma (EuroNet-
PHL) trials
EuroNet-PHL- C1 Low (TG1) Nonrandomized response- All: 2 ⫻ OEPA AR: none; IR: 19.8 Study completed, results
(recently completed) based RT Gy IF under evaluation
Intermediate Randomized chemotherapy 2 ⫻ OEPA ⫹ 2 ⫻ AR: no RT IR: 19.8 Study completed, results
(TG2) allocation with COPP/COPDAC Gy IF under evaluation
response-based RT
High (TG3) Randomized chemotherapy 2 ⫻ OEPA ⫹ 4 ⫻ AR: none; IR: 19.8 Study completed, results
allocation with COPP/COPDAC Gy IF under evaluation
response-based RT
EuroNet-PHL C2 Low (TL1) Nonrandomized response- AR: 2 ⫻ OEPA ⫹ AR: none; IR: 19.8 Patients in AR at early
(projected to open based therapy allocation 1 ⫻ COPDAC-28 Gy IF response assessment
Spring 2015) IR: 2 ⫻ OEPA receive one additional
cycle of COPDAC;
patients in IR receive
standard IFRT (19.8 Gy
to IF)
Intermediate Randomized chemotherapy 2 ⫻ OEPA ⫹ 2 ⫻ AR: none; IR/LRA: TL2 patients are randomly
(TL2) allocation and response- COPDAC-28/ 2 ⫻ COPDAC: 19.8 assigned between
based RT DECOPDAC-21 Gy IF ⫹ 10 Gy standard (COPDAC) and
boost to LRA intensified (DECOPDAC)
PET-positive chemotherapy; late
sites response assessment at
DECOPDAC: 30 the end of all
Gy to LRA PET- chemotherapy is only
positive sites done for patients with
IR after OEPA
High (TL3) Randomized chemotherapy 2 ⫻ OEPA ⫹ 4 v AR: none; IR/LRA TL3 patients are randomly
allocation and response- COPDAC-28/ 4 ⫻ (COPDAC): 19.8 assigned between
based RT DECOPDAC-21 Gy IF ⫹ 10 Gy standard (COPDAC) and
boost to LRA intensified (DECOPDAC)
PET-positive chemotherapy; late
sites; response assessment at
(DECOPDAC): the end of all
30 Gy to LRA chemotherapy is only
PET-positive done for patients with
sites IR after OEPA
(continued on following page)

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1, 2015 of Clinical Oncology. All rights reserved.
from 131.111.164.128
 Mauz-Körholz et al

Table A1. Summary of Recently Completed but Not Yet Evaluated, Ongoing, and Future First-Line Treatment Trials in Pediatric Classical
Hodgkin Lymphoma (continued)
Study Risk Design Chemotherapyⴱ Radiation Comments
St Jude–Stanford–Dana
Farber consortium
trials
HOD99 (recently High Nonrandomized, response- Stanford V CR: 15 Gy IF; Study completed, results
completed) based RT ⬍ CR: 25 Gy IF under evaluation
HOD05 (recently Intermediate Nonrandomized, response- Stanford V CR: 15 Gy IF; Study completed, results
completed) based RT ⬍ CR: 25 Gy IF under evaluation
HOD08 (ongoing) Low Nonrandomized, response- Reduced Stanford V CR: none; ⬍ CR: Ongoing trial
based RT 25 Gy TF
HOD13 (ongoing) High Nonrandomized, response- 2 ⫻ AEPA ⫹ 4 ⫻ CR: none; ⬍ CR: Ongoing trial
based RT CAPDAC 25 Gy TF
AHOPCA consortium trials
LH 2009 Low Nonrandomized, response- 4 ⫻ ABVD CR: none; ⬍ CR: Patients in CR after four
based RT 25 Gy IF cycles do not receive
RT
Intermediate Nonrandomized, response- 6 ⫻ ABVD CR: none; ⬍ CR: Sites in CR after two
based RT 25 Gy IF cycles of ABVD do not
receive RT
High Nonrandomized, response- Stanford V CR: 15 Gy IF; Study completed, results
based RT ⬍ CR: 25 Gy IF under evaluation but
appear to not be
acceptable at
approximately only 60%
event-free survival
High Nonrandomized, response- 2 ⫻ OEPA ⫹ 4 ⫻ CR: 20 Gy IF; Ongoing trial, aim to
based RT COPDAC ⬍ CR: 25 Gy IF improve event free
survival compared to
historical control with
Stanford V

Abbreviations: ABVE-PC, doxorubicin 50 mg/m2, bleomycin 15 IU/m2, vincristine 2.8 mg/m2, etoposide 375 mg/m2; prednisone 280 mg/m2, cyclophosphamide
1,200 mg/m2; AEPA, Adcetris (brentuximab vedotin) 3.6 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; AR, adequate response after
two cycles of initial OEPA chemotherapy (ie, PET(⫺) and at least 50% volume reduction in all initially involved sites; Bv-AVE-PC, brentuximab vedotin 1.8 mg/kg,
doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, etoposide 375 mg/m2, prednisone 280 mg/m2, cyclophosphamide 1,200 mg/m2; CAPDAC, cyclophosphamide 1,000
mg/m2, Adcetris (brentuximab vedotin) 2.4 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; COPDAC-28 (28-day cycle), cyclophosphamide 1,000 mg/m2,
vincristine 3.6 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; CR, complete remission; DECOPDAC-21 (21-day cycle), doxorubicin 25 mg/m2, etoposide
300 mg/m2, prednisone 320 mg/m2, dacarbazine 750 mg/m2; IF, involved field; IR: inadequate response after two cycles of initial OEPA chemotherapy (ie,
PET-positive and no progression in at least one initially involved site; ISRT, involved-site radiotherapy; IV, ifosphamide 12,000 mg/m2, vinorelbine 50 mg/m2; OEPA,
vincristine 5.4 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; PET, positron emission tomography; RER, rapid early responder; SER,
slow early responder; Stanford V, doxorubicin 125 mg/m2, vinblastine 30 mg/m2, bleomycin 30 IU/m2, vincristine 8.4 mg/m2, etoposide 360 mg/m2, prednisone 3,000
mg/m2, cyclophosphamide 1,800 mg/m2; TF, tailored field.
ⴱ
All drug doses are shown as cumulative doses per cycle, except for Stanford V, for which cumulative drug doses for the entire regimen are given.

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