ORIGINAL ARTICLE
Children and Adolescent Hodgkin Lymphoma in Argentina:
Long-term Results After Combined ABVD and Restricted
Radiotherapy
Pedro A. Zubizarreta, MD, Elizabeth Alfaro, MD, Myriam Guitter, MD,
Cristian Sanchez La Rosa, MD, María L. Galluzzo, MD, Natalia Millán, MD,
Fernando Fiandrino, MD, and María S. Felice, MD
Objective: Prospective analysis of clinical characteristics and long-
term treatment results of a pediatric cohort with Hodgkin lymphoma
(HL) treated in a single institution with ABVD and restricted
radiotherapy (RT).
Patients and Methods: Between September 2000 and December 2015,
165 new consecutive assessable patients with HL were registered at our
institution. Lymphocyte predominant nodular HL was excluded. Low
risk (LR) patients were stage I and IIA (no bulky disease, <4 involved
ganglionar areas and no lung hilar nodes), high risk (HR) was assigned
to stage IV and any other stage with bulky mediastinum. The rest of
the cohort was treated as intermediate risk (IR). Chemotherapy for LR
and IR patients was 4 and 6 courses of ABVD regimen, respectively.
These subsets received Low-dose involved field radiotherapy only in
case of partial remission at the end of chemotherapy (21 Gy in initially
involved areas, plus 14 Gy boost on residual disease). The HR group
was treated with 6 courses of ABVD followed always with 21 Gy
involved field radiotherapy if complete remission (CR) was achieved.
A boost of 14 Gy was added to residual disease in case of partial
remission.
Results: Median age was 10.6 years (range, 2.7 to 17 y). Males: 117
(71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76
(46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine
(30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%)
to HR. Forty-three patients (26%) had “bulky” mediastinum
involvement. One hundred thirty (79%) patients achieved CR after
chemotherapy and 161 (98%) after RT. Four patients (all HR), did
not respond to initial therapy and died of disease. One patient died
in first CR due to adenovirus infection on previously therapy-
related damaged lungs. Seventeen (10%) patients relapsed and 13 of
them remained in second CR after further therapy. Seventy-six
(46%) patients could be spared from RT and cured of disease (88%
of LR patients and 67% of IR patients). With a median follow-up of
5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95
(SE: 0.02), respectively. Overall survival according to risk group was
1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late
effects due to therapy were not significant.
Conclusions: The strategy of avoiding RT for LR and IR patients
that responded completely to ABVD chemotherapy achieved very
good results. For the HR group, the combination of 6 cycles of
ABVD and Low-dose involved field radiotherapy was efficacious
with similar good results. Nearly half of the patients could be cured
without RT.
Received for publication January 2, 2017; accepted July 10, 2017.
From the Hematology and Oncology Department, Pathology Department,
Radiotherapy Department, Hospital de Pediatría SAMIC “Prof.
Dr Juan P. Garrahan,” Buenos Aires, Argentina.
The authors declare no conflict of interest.
Reprints: Pedro A. Zubizarreta, MD, Hematology and Oncology Depart-
ment, Hospital de Pediatría Garrahan, Combate de los Pozos 1881, 1245
Buenos Aires, Argentina (e-mail: pedro.zubizarreta@hotmail.com).
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Key Words: Hodgkin lymphoma, childhood and adolescence, trial
results
(J Pediatr Hematol Oncol 2017;39:602–608)
A n average of 65 new Hodgkin lymphoma (HL) cases are
registered annually in Argentina, accounting for 5% of
all malignant diseases occurring in patients below 15 years of
age for the period 2000 to 2013.1 The estimated 3-year survival
rate for this population was 91%.1 In developed countries
5-year survival estimates largely exceeds 90%. Notwithstanding
long-term overall survival (OS) continues to decline mainly due
to therapy-related late effects. Therefore, the principal aim in
treating children and adolescents with HL should be to reduce
long-term morbidity and mortality from both chemotherapy
and radiation while maintaining OS. This approach has
resulted in the development of various strategies to identify the
best therapeutic balance.
A wide variety of drug combinations has been used and
effective chemotherapy schedules developed, avoiding toxic
and cumulative doses. A major late effect among survivors
of pediatric HL is an increased risk for second malignant
tumors, particularly breast cancer or other solid tumors,
which commonly occur in previously irradiated fields, so a
major currently goal in pediatric therapy is to reduce radiation
exposure. Extended field irradiation with higher doses was
worldwide replaced by Low-dose involved field radiotherapy
(LDIFRT). ABVD chemotherapy regime, although widely
used in adult HL, is scarcely reported in pediatric patients.
Pediatric HL results are usually published showing
survival results at 3 to 5 years, thus not reflecting long-term
therapy-related adverse events. CCG 5942 protocol and
GPOH-HD95 were nice exceptions to this rule because
10-year follow-up data were recently reported, allowing to
obtain most interesting conclusions mainly regarding the
late impact of radiotherapy (RT) in OS.2,3
We are reporting single institution long-term prospective
therapy trial results in a pediatric HL population using ABVD
as baseline chemotherapy and restricted RT in the trait of
CCG 5942 protocol.
PATIENTS AND METHODS
Children and adolescents younger than 17 years with
newly diagnosed HL were prospectively followed at Hospital
de Pediatría Garrahan (Buenos Aires, Argentina) following
the guidelines of Protocol LH-HPG 2000. Hospital Garrahan
is a tertiary care pediatric public center with 550 beds, with
J Pediatr Hematol Oncol  Volume 39, Number 8, November 2017 Pediatric Hodgkin Results with ABVD and Radiotherapy

special assistance on oncology and hematology patients, as
well as children undergoing cardiac surgery or neurosurgery.
After treating HL with national GATLA protocols
that used chemotherapy schedules with toxic alkylating
agents and extended field high-dose RT, a new philosophy
was adopted inspired on CCG 5942 protocol.4–6 Staging was
based on clinical evaluation (ie, computed tomography,
ultrasonography, and nonmandatory Ga67 radioisotopic
scan). Stages were as defined by the Ann Arbor staging
system.7 Patients were also classified with respect to the
absence or presence of 1 or more of the following systemic
signs and symptoms: unexplained loss of > 10% of body
weight, unexplained recurrent fever > 38°C, and drenching
night sweats. In addition, patients were classified according
to the presence or absence of the following adverse features:
hilar adenopathy, involvement of 4 or more nodal regions,
presence of a mediastinal tumor with a diameter equal or
greater than one third of the intrathoracic diameter, and
presence of an extra thoracic nodal mass with a maximum
diameter ≥ 10 cm. Pathologic material was classified according
to World Health Organization criteria. The clinical staging and
initial features described previously were used to assign patients
to 1 of 3 treatment groups. Low risk (LR) (group 1) comprised
all stage I and IIA patients who lacked adverse features. High
risk (group 3) comprised all stage IV and patients with bulky
mediastinum. Intermediate risk (IR) (group 2) comprised
patients who did not meet the criteria for the other 2 groups
(Table 1). Group 1 and 2 patients received 4 and 6 courses of
ABVD chemotherapy protocol at 28-day intervals, respectively
(Table 1). All these patients who achieved a complete remission
after chemotherapy did not receive any additional therapy.
Group 3 patients received 6 courses of ABVD chemotherapy. If
complete remission (CR) was achieved, RT was scheduled to
begin 4 weeks after completion of chemotherapy. A total dose
of 21 Gy was given to all involved fields. Stage IV patients with
pulmonary involvement received 10.5 Gy to the lungs. In case
of partial response (PR) after chemotherapy, all groups of
patients received baseline involved field RT plus a boost of
14 Gy to the field with residual disease (Table 1).
CR to chemotherapy was defined on the basis of reso-
lution of clinical, radiologic, and radioisotopic (Ga67) evidence of
disease at completion of chemotherapy. If there was an incom-
plete radiologic response in the mediastinum or abdomen,
response could still be classified as complete, provided that the
initial tumor volume was reduced by more than 70% (response
measured by computed tomography in 2 dimensions) and any
postchemotherapy residual mass that was initially gallium pos-
itive had converted to gallium negative. Patients who had 50% to
70% reduction in tumor volume were considered partial res-
ponders. Progressive disease was defined as clinical or radio-
graphic evidence of increased tumor volume in a previously
involved site or as involvement of a new site while the patient
received initial chemotherapy; no response was defined as a
<50% tumor reduction after initial chemotherapy. Relapse was
defined as the recurrence of HL, pathologically confirmed, after
complete remission to initial chemotherapy and RT schedule.
The Common Terminology Criteria for Adverse Events
v4.0 from the NCI (USA) were used when data were analyzed
in 2016 to classify toxic findings prospectively collected.8
Long-term toxicities were identified with thyroid
function tests (every 6 mo). Pulmonary function studies with
diffusing capacity of the lungs for carbon monoxide were
performed every 6 months during the first 2 years, then
stopped if persistently normal, or 2 years after stabilization or
test improvement, whenever any abnormality was detected after
therapy. Cardiac contractility was evaluated every year during

TABLE 1. Clinical Group Setting and Therapy Schedule

Group 1, low risk
Stage I patients without adverse disease features*
Stage II patients without adverse disease features* and without clinical “B” symptoms†
Group 2, intermediate risk
Stage I patients with adverse disease features,* with the exception of bulky mediastinum
Stage II patients with adverse disease features* and/or with clinical B symptoms†
Stage III patients
Group 3, high risk
Stage IV and any stage with bulky mediastinum patients‡
Low risk, group 1: stages I and IIA without risk factors
ABVD 4 courses Complete remission: no further therapy
Partial remission: 21 Gy IFRT, plus 14 Gy boost on residual mass
Intermediate risk, group 2: stages I and IIA with risk factors, stages IIB and III
ABVD 6 courses Complete remission: no further therapy
Partial remission: 21 Gy IFRT, plus 14 Gy boost on residual mass
High risk, group 3: stage IV, any stage with bulky mediastinum
ABVD 6 courses Complete remission: 21 Gy IFRT
Partial remission: 21 Gy IFRT, plus 14 Gy boost on residual mass
ABVD regime
Doxorubicin: 25 mg/m2 IV: days 1 and 15
Vinblastine: 6 mg/m2 IV: days 1 and 15
Bleomycin: 10 IU/m2 IV: days 1 and 15
Dacarbazine 375 mg/m2 IV: days 1 and 15
Every 28 days if absolute neutrophil count > 750/μL and platelet count > 75,000/μL.
*Adverse disease features comprise 1 or more of the following: hilar adenopathy, involvement of 4 or more nodal regions, and node or nodal aggregate with a
diameter > 10 cm.
†Clinical B symptoms comprise 1 or more of the following: unexplained loss of more than 10% of body weight, unexplained recurrent fever > 38°C, and
drenching night sweats.
‡A mediastinal tumor with diameter greater than or equal to one third of the chest diameter was considered bulky.
IFRT indicates involved field radiotherapy.

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Zubizarreta et al
the first 3 years then every 2 years. Lung toxicity, usually acute or
subacute, did not need to be continuously followed once it
subsided. Contrariwise, cardiac contractility and cardiovascular
status was to be looked after for life. Long-term toxicity needs of
follow-up were transmitted to patients and parents.
The initial surrogate end point was event-free survival
(EFS), defined as the minimum time to disease relapse,
progression, occurrence of a nonthyroidal second malignant
neoplasm, or death from any cause. The primary end point
was OS, defined as the time to death from any cause. These
end points were measured from the time of study entry, or
the time of CR, as appropriate. Patients not achieving a
complete remission or PR or showing evidence of pro-
gressive disease with initial therapy were considered a
treatment failure and censored at time 0 for EFS analysis.
Survival estimates were based on the product-limit estimator
with Greenwood SEs.9 Comparisons between survival
curves were based on the log-rank test.10 For statistical
analysis Graph Pad Prism version 4.00, for Windows
(Graph Pad Software, San Diego, CA, 2003) was used.
Analyses are based on follow-up available as of May
1, 2016.
The protocol guidelines were approved by the institutional
ethical and research committee. Written informed consent was
obtained from parents, and/or guardians.
RESULTS
From September 2000 to December 2015, 211 new con-
secutive patients with diagnosis of HL were registered. Forty-six
patients were deemed not assessable: lymphocyte predominant
nodular HL (n = 14), treated with other chemotherapy or in
other institutions (n = 13), on treatment: (n = 7), diagnostic error
(n = 2 non-HL), human immunodeficiency virus (n = 2), without
diagnostic pathology certainty (n = 1), composite lymphoma
(n = 1, HL/non-Hodgkin diffuse large B-cell lymphoma),
ataxia telangiectasia treated with Vinblastine, Doxorubicin,
Methotrexate, Prednisone (n = 1), hypogammaglobulinemia
(n = 1), HL postliver transplantation (n = 1), HL associated to
liver ductopenia (n = 1), HL associated to severe pemphigus
(n = 1), very early lost to follow-up (n = 1).
One hundred sixty-five patients remained assessable
for the present analysis, median age 10.6 years (range, 2.7
to 17 y); 117 (71%) were males and 48 (29%) females
(M/F = 2.4). Most patients (75.2%) had nodular sclerosis
(n = 124), mixed cellularity was found in 32 (19.4%) patients
and only 3 (1.8%) classic lymphocyte-rich histology. Stage II
disease (46%) was more frequent and 75 patients (45%)
had B symptoms which were more common in advanced
disease (Fig. 1). Bulky mediastinal disease was present in 43
(26%) patients. Thirty-five (21%) stage IV patients displayed
hematogenous disease in the lungs (n = 23), liver (n = 11),
bone marrow (n = 11), bone (n = 7), and thyroid (n = 2). Five
patients had hemolytic anemia at onset, 3 nephrotic syndromes,
and 1 diabetes mellitus, all deemed to be autoimmune-associated
disease which immediately disappeared with Hodgkin therapy.
Risk group allocation of patients was as follows: group
1: 49 (30%), group 2: 49 (30%), and group 3: 67 (40%)
(Table 2).
Complete remission was achieved in 130 (79%) of
assessable patients after chemotherapy (98% for LR, 80%
for IR, and 64% for high risk [HR]). The addition of
LDIFRT for PR disease following the protocol guidelines
raised the CR rate to 97.6% (n = 161) for the whole cohort
(Table 2). Four patients (2.4%) with advanced disease
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J Pediatr Hematol Oncol  Volume 39, Number 8, November 2017
80
70
60
50
40
B
30
A
20
10
0
Stage I Stage II Stage III Stage IV
n=18 n= 76 n= 35 n= 35
(11%) (46%) (21%) (21%)
FIGURE 1. Distribution according to Ann Arbor staging and
presence of B symptoms.
(group 3) did not respond to initial therapy. They did
not respond to further therapy and died of disease with a
significant difference in a comparison with all other events
in terms of OS outcome (log-rank test: P = 0.001). In the
overall cohort, there were 22 first events, of which 10%
(n = 17) were relapses and 2.4% (n = 4) initial refractory HL,
and 0.6% (n = 1) was a death in CR (adenovirus on a pre-
viously damaged lung) (Table 2).
Relapse occurred in 10% of cases (n = 17) mainly in
nonirradiated patients (n = 11), thus allowing the use of a
combined conventional treatment that achieved a high rate
of disease rescue. Median time to relapse after achieving CR
was 20.9 months (range, 2.4 to 49.6 mo). One patient was
rescued with RT alone. Eight patients were salvaged with
second-line chemotherapy and RT (LR: 5, IR: 2, and HR:
1). High-dose chemotherapy was used as part of the salvage
therapy in 6 relapsed cases of which 4 could be rescued with
long-term continuous CR. So 76% of all relapsed patients
(13/17) achieved continuous CR. Table 2 describes salvage
therapy only for relapsed cases. High-dose chemotherapy,
followed by autologous stem cell rescue, was also used in 1
initially nonresponder who achieved a very good PR.
To date, a total of 9 deaths (5.5%) were reported, 8
disease related, and 1 who died in CR. All 4 HR patients who
did not respond to initial therapy died of disease, being a
characteristic subset of refractory HL with ominous outcome.
There were no therapy-related malignant diseases with
the only exception of a secondary thyroid papillary carci-
noma, successfully treated with surgery and I131 and not
considered as an event for survival analysis.
For the 165 eligible patients, with a median follow-up
of 60 months, the 5-year EFS and OS estimates were 0.84
(SE = 0.03) and 0.95 (SE = 0.02), respectively (Fig. 2). For
patients assigned to clinical groups 1, 2, and 3, the 10-year
EFS estimates from date of CR were 0.88 (SE = 0.05), 0.84
(SE = 0.05), and 0.82 (SE = 0.05), respectively, and the
10-year OS estimates from study entry were 1, 0.93 (SE =
0.05), and 0.85 (SE = 0.06), respectively.
Table 3 shows a most important issue: 76 patients from
LR and IR groups could be cured without any exposure to
RT. This is 46% of the whole cohort of patients, and 77.6%
of low and intermediate cases.
J Pediatr Hematol Oncol  Volume 39, Number 8, November 2017 Pediatric Hodgkin Results with ABVD and Radiotherapy

CCR indicates continuous complete remission; chemo, chemotherapy; CR, complete remission; DCR, dead in complete remission; DOD, dead of disease; HDCh, high-dose chemotherapy; NR, nonremission; RT,
The outcome of bulky mediastinal disease was as good

Deaths (n

DOD: 2

DOD: 6
DCR: 1
9 (4.5)
(28.6)
as the rest of the cohort [EFS comparison: log-rank test

[%])
No
P = 0.85, (Fig. 3)].
The acute hematological toxicity of ABVD regime was
mild. Although grade I to II (56% of courses) and grade III
(n [% of Relapses] to IV leukopenia (26%) and grade I to II (34%) and grade III
Second CCR

to IV neutropenia (31%) were detected, they lasted just a few

5 (71)

3 (60)

13 (76)
5 (100)
days, and fever and neutropenia occurred only in 2.1% of
courses. Grade I anemia or thrombocytopenia were detected
in only 4% of ABVD courses.
Lung toxicity was observed in 19 (11.5%) cases. Five cases
were detected after bleomycin administration. But most of them
developed after the addition of thoracic irradiation (n = 13) and
were prospectively followed and studied by specific function lung
Chemo+RT: 2 chemo+RT
1 chemo+RT+HDCh: 3
7 (6 without initial RT) Chemo+RT: 3 RT alone:
Second-line Therapy

tests evaluating alveolar diffusion diffusing capacity of the lungs

Chemo+RT: 5

for carbon monoxide. Most cases were moderate (n = 15) and

for Relapse

subsided with corticoid therapy, recovering normal functional

tests during the following 2 years after finishing therapy. One
—
+HDCh: 3

patient died in CR due to a superimposed adenovirus after fin-

ishing corticotherapy.
Thyroid toxicity was found after cervical irradiation in
32 (19.4%) patients who displayed evidence of subclinical
hypothyroidism. Two patients (1.2%) developed a thyroid
5 (all without initial RT)

neoplasia (1 adenoma and 1 papillary carcinoma) and were

successfully treated with thyroidectomy. To note: 1 patient
Relapse (n [%])

developed a hyperthyroidism (Graves-Basedow disease) and

in 5 patients without neck RT subclinical hypothyroidism
17 (10)
5 (7.5)
(10)

(14)

was also detected due to autoimmune disease. A colon

adenoma in a boy and a juvenile granulose cell tumor in a
girl were detected in nonirradiated regions.
Other incidental complications were also found: inter-
nal jugular vein thrombosis (1 patient), moderate impair-
ment of cardiac contractibility (1 patient treated with
CR: 161 (97.6) NR: 4 (2.4)
CR = 63 (94%) NR = 4 (6)

carvedilol with favorable outcome), avascular necrosis of

Response (n [%])

irradiated hip (1 patient) and grade 3 neuropathic pain

CR = 49 (100)

CR = 49 (100)

(1 patient).
Overall
TABLE 2. Therapy Response and Overall Outcome According to Risk Stratification

DISCUSSION
Excellent results were obtained in pediatric and ado-
lescent HL with combined chemotherapy and RT.11–15
The balance in children and adolescent HL therapy has
not been established yet.16,17 Excess mortality from second
Chemo+RT (n [%])

neoplasms and cardiovascular disease varies by sex and

persists more than 20 years of follow-up in childhood HL
CR After

10 (20)

20 (30)

31 (19)
1 (2)

survivors.18
Over the last 3 decades, all major pediatric and several
adult HL study groups have followed the paradigm of
response-based treatment adaptation with reduction or
elimination of RT and tailoring chemotherapy toxicity.
Refinement and reduction of RT have been implemented on
Risk Group (n) Chemotherapy (n [%])

the basis of results from collaborative group studies, so that

radiation could be completely eliminated for certain sub-
groups of patients.19
CR After

48 (98)

39 (80)

43 (64)

130 (79)

Long-term pediatric therapy results in HL lymphoma

treated with ABVD baseline chemotherapy have not been
usually reported. This is somewhat curious, considering the
voluminous experience with ABVD in adults.
Female predominance is particularly observed in late
adolescence and young adults. In high income countries, HL
Total (n = 165)

childhood and adolescent series have a median onset age

High (n = 67)
Low (n = 49)

Intermediate

radiotherapy.

above 14 years. A middle income country as Argentina

(n = 49)

showed a lower median age in our consecutive series

(10.6 y). This is in line with a higher male to female ratio
(2.4) and earlier population contact with the EBV.

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Zubizarreta et al J Pediatr Hematol Oncol  Volume 39, Number 8, November 2017

1.0 Similar results were published by Dr Dörffel and colleagues

0.9 reporting on the results of Protocol GPOH-HD95. For the small
5 y Survival Estimates

0.8 subset of patients who entered CR with chemotherapy, no dif-

ferences in OS were observed when compared with the irradiated
(Standard Error)

0.7
0.6
0.5 OS: 0.95 (SE: 0,02), deaths: 9
0.4
0.3 EFS: 0.84 (SE: 0,03), events: 22
0.2
0.1
0.0
0 50 100 150
Months
FIGURE 2. Five-year event-free (EFS) and overall survival (OS)
estimates, n = 165, median follow-up = 60 months.
Advanced disease was more frequent in our setting due to
the referral of these usually undiagnosed cases. As expected,
the CR rate after chemotherapy in our setting was inversely
correlated with tumor burden. The addition of LDIFRT for
PR disease raised the CR rate to 97.6% for the whole cohort
(Table 2). Initial refractory disease was observed in 4 cases
(2.4%) and all died of disease progression, proving to be a
very bad prognostic factor in HL. This small subset of
patients should be rapidly identified to initiate new therapy
strategies that may improve its otherwise dismal outcome.
Relapse rate was 10% (n = 17) for the whole cohort.
Seventy-six percent (n = 13) of relapsed patients could be
rescued with RT alone (1 patient) or second-line chemotherapy
that did not add major toxicity plus RT (n = 8). The addition
of high-dose chemotherapy followed by autologous stem cell
infusion was used in 4 cases (Table 2).
Our series combined chemotherapy and RT only in the
HR group. RT was not delivered when a CR was obtained in
LR and IR group after ABVD. This strategy was inspired in
Protocol CCG 5942 that randomized use of RT after complete
remission using the hybrid COPP/ABV regime for LR and IR
and a more intensive multidrug chemotherapy for HR patients.
An early 3-year initial report showed a significant difference in
EFS in favor of the RT arm that precluded further accrual
following the Protocol stopping rules.6 In 2010 Dr Wolden and
colleagues reported no difference in OS between both arms
of the same cohort of patients. In an as-treated analysis for
randomly assigned patients, the 10-year EFS and OS rates were
91.2% and 97.1%, respectively, for involved field radiotherapy
and 82.9% and 95.9%, respectively, for no further therapy
(EFS and OS comparisons, P = 0.004 and 0.50, respectively).
EFS survival differences by risk stratification only remained
significant for the LR group.2
majority and the only differences in EFS remained for the IR
group. But these findings may be due to some bias considering
that RT was not randomized and perhaps the best responders
could have been selected for no RT after chemotherapy results.3
OS is the gold standard for evaluation of treatment
efficacy and the cornerstone to build up any advance in
cancer therapeutics. OS is accurate for event and time and it
takes into account both safety (toxicity) and efficacy (disease
outcome). EFS is a surrogate end point that allows an earlier
200 assessment of results, but its validity requires confirmation
with long-term OS. A 10-year survival analysis expresses the
weight of late over early mortality and begins to shows the
impact of RT late effects that have no plateau in longer
follow-up.20,21
The outcome of our series was excellent. No differences
in EFS estimates were found between patients with and
without bulky mediastinum in our setting, taking into
account that all bulky mediastinum cases received RT
(Fig. 3). In CCG 5942, bulk disease was a risk factor for
significantly lower10-year EFS. This may be indicating that
the addition of RT was able to eradicate residual bulky
disease more efficiently than chemotherapy. Longer or more
intensive multidrug chemotherapy may also overcome this
particular resistance.
ABVD regime is the gold standard chemotherapy in
adult HL and has low acute and late toxic complications.
Hematologic toxicity was short termed and permitted an
easy ambulatory management with excellent family and
patient adherence and very low rate of fever and neutropenia.
This regime has lower impact on male fertility than other
schemes with more toxic alkylating agents. We did not find any
significant heart toxicity so far. The cumulative dose of doxor-
ubicin raises concern on cardiac contractility in the long term, but
if RT is avoided the potentiation of this late effect is reduced.
Lung toxicity was the main concern in this protocol and the cause
of the only death in CR in our setting. However, lung toxicity
was mainly acute and temporary for the rest of the patients, with
very good long-term functional evolution using appropriate
corticoid therapy. The rate of advanced hematogenous lung
involvement and bulky mediastinum disease was high in our
population, so the impact of bleomycin was potentiated by the
administration of lung and mediastinum RT.
Thyroid toxicity was high among patients with neck
irradiation. Subclinical hypothyroidism was always detected
by systematic prospective laboratory testing. One case of
papillary carcinoma was successfully treated with thyroidectomy
and therapeutic radioactive iodine. Another boy developed a

TABLE 3. Radiotherapy Exposition

n (%)
Risk Group (n) IFRT (21 Gy) RT for PR (35 Gy) RT for Rel (35 Gy) Total RT RT Spared
Low risk (49) — 1 (2) 5 (10) 6 (12) 43 (88)
Intermediate (49) — 10 (20) 6 (13) 16 (33) 33 (67)
High risk (67) 43 (64) 24 (36) Rel 5 NR 4 67 (100) None
Total (165) 43 (26) 35 (21) 11 (7) 89 (54) 76 (46)
IFRT indicates involved field radiotherapy; NR, nonremission; PR, partial response; Rel, relapse; RT, radiotherapy.

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J Pediatr Hematol Oncol  Volume 39, Number 8, November 2017
1.0
0.9
0.8
Survival estimates
0.7
0.6
0.5 No bulky mediastinum: EFS: 0.85
(SE: 0.06) n:122, events: 17
0.4
0.3
Bulky mediastinum: EFS: 0.84
0.2 (SE: 0.05), n: 43, events: 5
0.1
0.0
0 50 100 150 200
Months
FIGURE 3. Event-free survival (EFS) estimates for Hodgkin lym-
phoma patients with and without initial bulky mediastinum, sur-
vival comparison: log-rank test P = 0.85, n = 165, median follow-
up = 60 months.
thyroid adenoma. Both of them remained without any further
complication and excellent quality of life.
No secondary hematopoietic malignancies were
detected, as expected after ABVD. Other neoplasias (ie,
juvenile granulosa cell tumor and a colon adenoma) outside
RT fields, could not be associated with therapy.
The most significant achievement of this trial was that
RT could be avoided in 46% of the whole cohort of patients
who had a long-term disease-free follow-up (Table 3).
New evidence in this trend is needed. After CCG 5942,
experience without RT has been timidly reported.22–24
EuroNet-PHL-C2 is actually exploring to avoid RT in good
responders to OEPA-COPDac baseline chemotherapy
incorporating early response assessment based on previous
EuroNet-PHL-C1 trial results. At the same time the impact
of a more intense regime (DECOPDac) to reduce relapse
events without irradiation is being evaluated.25
The key question in pediatric HL therapy is whether
10% of relapses should be tolerated, knowing that most
patients can be rescued with nonhighly toxic chemotherapy
alternatives and combined RT, obtaining no different OS in
the long run but sparing from radiation nearly 80% of the
whole population.
In conclusion: The strategy of avoiding RT for LR and
IR patients that responded completely to ABVD chemo-
therapy achieved very good results. For HR group, the
combination of 6 cycles of ABVD and LDIFRT was effi-
cacious with similar good results. Half of the patients could
be cured without RT.
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