Radiotherapy of Hodgkin Lymphoma:

Indications, New Fields, and Techniques

Theodore Girinsky, MD, and Mithra Ghalibafian, MD

In recent years, radiotherapy in patients with Hodgkin lymphoma has evolved considerably
because of sophisticated imaging technologies and radiation delivery techniques. Even
more recently, a new radiation field concept has emerged to ensure better normal tissue
protection while preserving an excellent clinical outcome. The role of radiation therapy is
also rapidly changing because the concept of a risk-adapted treatment strategy, in which
combined-modality treatments were the order of the day, is now expanding into a concept
of response-adapted treatments.
Semin Radiat Oncol 17:206-222 2007 Elsevier Inc. All rights reserved.

I n the last decade, radiation treatments delivered to pa-

tients with Hodgkin lymphoma (HL) have evolved pro-
foundly in terms of radiation doses, fields, and techniques.
This evolution became indispensable because of the occur-
rence of late complications.1-7 Currently, there is a wide-
spread belief that combined-modality treatment can se-
cure a favorable clinical outcome while minimizing late
toxicity. On the other hand, some authors presume that
chemotherapy alone, without life-threatening toxicity,
would be sufficient in most cases.8 It is, however, note-
worthy that most of the ongoing randomized studies are
either investigating a reduction in the number of chemo-
therapy drugs9 or cycles10,11 or radiation doses11 in a com-
bined-modality setting or exploring the concept of re-
sponse-adapted treatments (European Organisation for
Research and Treatment of Cancer [EORTC]Group
dEtudes des Lymphomes de lAdulte [GELA] H10 and
Manchester trials in which radiation treatment is omitted
if a functional complete remission is achieved on [18F]
2-fluoro-2-deoxy-D-glucose [FDG-PET]). Furthermore,
combining our experience with that of pediatric oncolo-
gists should allow us to make further conceptual changes
in the treatment of HL.
Department of Radiation Oncology, Institut Gustave Roussy, Villejuif,
France
Address reprint requests to Theodore Girinsky, MD, Department of Radia-
tion Oncology, Institut Gustave Roussy, 39 rue Camille Desmoulins,
94805 Villejuif, France. E-mail: girinsky@igr.fr
Current State-of-the-Art: Risk-
Adapted Treatment Strategies
Prognostic Factors
Currently, treatments are based on well-known prognostic
factors in early stages with little variance between the various
international groups. An international prognostic score has
also been devised for advanced stages (Table 1).12
Early-Stage HL
The Advent of Combined-Modality Treatments
With the exception of lymphocyte predominant HL, radio-
therapy alone is no longer recommended as the standard
treatment in HL (Table 2). Many studies have evinced its
inferiority over combined treatments and indicated that
late complications are closely correlated with radiation
doses and field sizes.1-7 In the EORTC H7 trial,13 the 10-
year event-free survival (EFS) rate was significantly lower
in the subtotal nodal irradiation (STNI) arm versus the
epirubicin, bleomycin, vinblastine, and prednisone
(EBVP) arm involved-field radiotherapy (IF-RT), 78%
and 88% respectively. In the Canadian trial,14 the 3-year
failure-free survival (FFS) rate was also significantly dif-
ferent, 81% and 94% in the STNI arm and the computed
tomography (CT) STNI arm, respectively. In the GHSG
HD7 trial, the 2-year freedom-from-treatment-failure rate
(FFTF) was 84% and 96% in the extended-field radiother-
apy (EF-RT) group and in the CT EF-RT group respec-
tively.15 In the EORTC-GELA H8-F randomized trial the
4-year treatment-failure-free survival (TFFS) rate was 77%
and 99% in the STNI group and CT IF-RT group, re-
spectively.16

206 1053-4296/07/$-see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.semradonc.2007.02.007
Radiotherapy of HL 207

Table 1 Risk Factors and Treatment Groups

Risk Factors Treatment Groups
Early stages
EORTC Large mediastinal mass Favorable: stage I-II without risk factors
Age > 50 yr Unfavorable: stage I-II with one or more
Elevated ESR, B symptoms* risk factors
4 or more involved regions
GHSG Large mediastinal mass Favorable: stage I-II without risk factors
3 or more involved regions Intermediate: stage I or stage IIA with 1
Elevated ESR, B symptoms* or more risk factors
Extranodal disease Stage IIB with elevated ESR and 3 or
more involved regions
ECOG AND NCI-C Histology (MC, LD) Favorable: stage I-II without risk factors
Age >40 y Unfavorable: stage I-II with one or more
Elevated ESR or B symptoms risk factors
4 or more involved regions
Advanced stages
International Prognostic Score Serum albumin <4 g/dL
Hemoglobin <10.5 g/dL
Male gender
Stage IV
Age >45 y
White cell count >15.103/mm3
Lymphocyte count <600/mm3
or <8% of white cell count
MC mixed cellularity; LD lymphocyte depleted.
*ESR (>50 without B symptoms or > 30 with B symptoms).

The Improvement of Combined-Modality Treatments
Favorable Early-Stage HL. Once combined-modality treat-
ment was accepted as a good alternative, most randomized
studies attempted to determine the best combination (Table
3). The Milan study17 showed that large radiation fields
(STNI) were unnecessary and that IF-RT was sufficient. The
following results must be considered as preliminary because
follow-up is rather short. The results of the German GHSG
HD10 trial18,19 tend to imply that 2 cycles of ABVD 20 Gy
IF-RT may be adequate in such patients. The results of the
EORTC-GELA H9 trial11 suggest that radiation treatment is
still needed in patients in CR or CRu after 6 cycles of EBVP
(the chemotherapy alone arm was closed before the end of
the trial) and also imply that a radiation dose of 20 Gy may
suffice. A longer follow-up is needed to confirm these early
results. A radiation dose of 30 Gy is now accepted as safe and
has provided excellent results in the Stanford group study.20
Improvement of chemotherapy regimens is also an important
aim. In the ongoing GHSG HD13 trial,9 drugs such as bleo-
mycin or dacarbazine are avoided. In summary, in this favor-
able group of patients, combined-modality treatment can still
be improved in terms of chemotherapy regimens and radia-
tion treatment parameters provided that a correct balance is
struck between these 2 treatment components.

Table 2 Radiotherapy Alone Versus Combined Treatment Modalities in Favorable Early-Stage Hodgkin Lymphoma
Trial Treatments Outcome Overall Survival
EORTC H7 10-y EFS* 10-y OS
STNI (36-40 GY) 78% 92%
6 EBVPIF RT (36-40 GY) 88% 92%
SWOG# 9133 3-y FFS* 3-y OS
STNI (36-40 GY) 81% 96%
3CT STNI 94% 98%
GHSG HD7 2-y FFTF* 2-y OS
EF RT 30 GY (IF 40GY) 84% 98%
2 ABVD EF RT 30 GY (IF 40 GY) 96% 98%
EORTC/GELA H8 4-y TFFS* 4-y OS
STNI 36 GY (IF 40 GY) 77% 95%
3MOPP/ABV IF RT (36 GY) 99% 99%
*Significantly different results.
Doxorubicin and vinblastine.
The final results presented at the 2002 ASH meeting were 75% and 91% for 5-year FFTF and OS was 94% in both groups.
208 T. Girinsky and M. Ghalibafian

Table 3 Combined-Modality Treatments in Favorable Early-Stage Hodgkin Lymphoma

Trial Treatments Outcome Overall Survival
MILAN Group* 12-y EFS 12-y OS
4ABVD STNI 30 GY (IF 36-40) 87% 96%
4ABVD IF RT (36-40 GY) 91% 94%
GHSG HD 10 2-y FFTF: 96.6% 2-y OS :98.5%
2ABVD IF RT 30 GY
2ABVD IF RT 20 GY
4ABVD IF RT 30 GY
4ABVD IF RT 20 GY
EORTC-GELA H9F 4-y EFS 4-y OS
6EBVP IF RT 36 GY 87% 98%
6EBVP IF RT 20 GY 84% 98%
6EBVP 70% 98%
*Early favorable and unfavorable groups.
Significant difference.

Unfavorably Early-Stage HL. During the last decades, the
international community has strived to optimize com-
bined-modality treatments by evaluating the most efficient
chemotherapy regimens, the optimal number of chemo-
therapy cycles, and the possibility of reducing radiation
field sizes (Table 4). The EORTC H8 trial10 established that
small radiation fields (IF-RT) could safely replace STNI in
such patients. The same results were yielded by the GHGS
HD 8 trial21 in which all nonbulky sites received 30 Gy of
IF-RT after 4 cycles of chemotherapy. The EORTC H7U13
showed that IF-RT was adequate provided chemotherapy
is efficacious enough (the EBVP arm fared significantly
worse than the mechlorethamine, vincristine, procarba-
zine, and prednisone [MOPP]/doxorubicin, bleomycin,
and vinblastine [ABV] arm). The most recent randomized
trials have focused on finding the optimal chemotherapy
and radiation treatments. The EORTC-GELA H9U trial11
investigated the number of chemotherapy cycles and reg-
imens. Chemotherapy was followed by IF-RT delivering
30 Gy in case of a CR or CRu and 36 to 40 Gy in case of a
partial remission (PR). The preliminary results suggest
that 4 adriamycin, bleomycin, vinblatine, and dacarbazine
(ABVD) IF-RT may be the best compromise given that
the cyclophosphamide, doxorubicin, etoposide, procarba-
zine, prednisone, vincristine, and bleomycin (BEACOPP)
regimen proved to be more toxic and no more effective
than the ABVD regimen. The GHSG HD11 trial22 provided
additional preliminary evidence with the ABVD regimen
yielding similar results to the BEACOPP regimen. How-
ever, because the 2-year freedom-from-treatment-failure
rate was considered rather low (89.9%), the ongoing
HD14 trial is currently testing ABVD combined with esca-
lated BEACOPP IF-RT (30 Gy).9 The GHSG HD11 trial
also suggested that a radiation dose of 20 Gy might be
sufficient (relapse rate of 5% and 7% in the 30 Gy and 20
Gy IF-RT groups, respectively). The follow-up of these 2

Table 4 Combined-Modality Treatments in Unfavorable Early Stages

Trial Treatments Outcome Overall Survival
EORTC-GELA H8-U 4-y TFFS 4-y OS
6MOPP/ABV IF RT (36-40 GY) 89% 90%
4MOPP/ABV IF RT (36-40 GY) 92% 94%
4MOPP/ABV STNI (36-40 GY) 92% 92%
GHGS HD 8 5-y FFTF 5-y OS
2COPP/ABVD EF RT 30 GY (bulk 40 GY) 86% 91%
2COPP/ABVD IF RT 30 GY (bulk 40 GY) 84% 92%
EORTC H7U 10-y EFS* 10-y OS*
6EBVP IF RT (36 GY) 68% 79%
6MOPP/ABV IF RT (36 GY) 88% 87%
EORTC-GELA H9U 4-y EFS 4-y OS
4ABVD IF RT 30 GY 89% 95%
6ABVD IF RT 30 GY 94% 96%
4 BEACOPP IF RT 30 GY 91% 93%
GHSG HD-11 2-y FFTF 89.9% 2-y OS 97.4%
4ABVD IF RT 30 GY
4ABVDIF RT 20 GY
4BEACOPPIF RT 30 GY
4BEACOPPIF RT 20 GY
*Significant differences.
Radiotherapy of HL 209

Table 5 Radiation Treatments in Advanced Hodgkin Lymphoma

Trials Design
GHSG 7-y FFFT 7-y OS
3COPP/ABVD 1 59.42% 76.2%
3COPP/ABVD RT (20 GY) 59.42% 76.2%
MUMBAI Trial* 8-y EFS 8-y OS
6ABVD 59% 80%
6ABVD RT (30 GY) 78% 100%
SWOG 5-y RFS 5-y OS
6MOP/BVP 66% 79%
6MOP/BVP RT (20 GY) 74% 86%
GELA-H89 10-y 10-y OS
DFS
8ABVPP 70% 90%
8MOPP/ABV 76% 78%
6MOPP/ABV STNI (30 GY) (IF RT: 35-40) 79% 82%
6ABVPP STNI (30 GY) (IF RT: 35-40) 76% 77%
EORTC H3-4 5-y EFS 5-y OS
CR 6-8MOPP/ABV 85% 91%
6-8MOPP/ABV RT (24 GY) 79% 85%
PR 6MOPP/ABV RT 79% 87%
*Results of the subgroup with advanced-stage disease.

randomized trials is rather short so no definitive conclu-
sions can be drawn as yet.
Advanced HL
The role of adjuvant radiotherapy in advanced stage HL
seems to be clearly defined (Table 5).
Patients in Complete
Remission After Effective Chemotherapy
Patients in complete remission after 4 to 6 cycles of effective
combination therapy required either adjuvant chemotherapy
or radiotherapy (20-30 Gy IF-RT) as shown by Diehl and
coworkers.23 Laskar and coworkers24 and Yahalom and co-
workers25 showed that adjuvant low-dose radiotherapy
(20-30 Gy) to all involved nodal sites was beneficial in terms
of relapse-free survival (RFS), event-free survival (EFS), and
overall survival (OS). However, in the Southwest Oncology
Group trial,26 the benefit obtained with adjuvant radiother-
apy was seen exclusively in a subgroup of patients (patients
with nodular sclerosis histology or bulky disease). A recent
large randomized study27 confirmed that adjuvant chemo-
therapy (2 cycles) yielded similar results to adjuvant radio-
therapy (STNI). However, there was a higher recurrence rate
in patients with bulky mediastinal masses treated with adju-
vant chemotherapy compared with patients treated with ad-
juvant radiotherapy.28 Furthermore, the EORTC trial29 con-
vincingly showed that patients in complete remission after 4
or 6 cycles of MOPP/ABV and receiving 2 additional chemo-
therapy cycles did not benefit from low-dose IF-RT (24 Gy).
It confirmed the meta-analysis performed by Loeffler and
coworkers,30 which suggested that chemotherapy alone was
sufficient provided that chemotherapy was given at a maxi-
mal number of cycles. However, a word of caution is neces-
sary because long-term results showed that patients treated

Table 6 Chemotherapy Alone Versus Combined-Modality Treatment

Trials Treatment Outcome Outcome
MSKCC 5-y FFP 5-y OS
IAB-IIAB-IIIA (no bulky disease) 6ABVD 81% 90%
6ABVD RT 36 GY 86% 97%
GATLA-GLATHEM 5-y DFS 5-y OS
I-II 6CVPP 62% 89%
6CVPP IF RT (30 GY) 71% 82%
NCIC-ECOG 5-y FFP 5-y OS
IA-IIA (no bulky disease)
Global strategy Includes RT 93%* 94%
ABVD alone 87%* 96%
Favorable STNI (35 GY) 88% 100%
Unfavorable 2ABVD STNI (35 GY) 95% 92%
CR after 2 cycles 4ABVD 87% 97%
No CR after 2 cycles 6ABVD 88% 95%
*Significantly different results
210
Figure 1 Determination of a CTV in a cervical area in CR or CRu after
chemotherapy.
with chemotherapy alone did not fare well. Duggan and co-
workers31 reported a 5-year FFS of only 63% in patients with
advanced disease treated with 8 to 10 cycles of ABVD or
MOPP/ABV alone. Furthermore, in this study, the MOPP/
ABV was found to be associated with significant toxicity and
is no longer recommended for patients with HL. Canellos and
Niedzwiecki32 showed that the FFS rate plummeted to 45%
at 15 years in patients treated with ABVD alone. On the other
hand, Horning and coworkers33 reported excellent results (a
Figure 2 (A) Yellow contouring outlines the initial volume on a prechemotherapy axial CT scan. (B) Red outlines the
PET areas on the prechemotherapy CT scan. (C) Initial volume superimposed on a postchemotherapy axial CT scan.
(D) Adequate CT contouring on the postchemotherapy CT scan (green contouring).
T. Girinsky and M. Ghalibafian
5-year FFP and OS of 89% and 96%, respectively) in patients
with advanced disease or with locally extensive mediastinal
stage I and II disease treated with the Stanford V chemother-
apy regimen (weekly for 12 weeks) and radiotherapy to initial
sites of bulky disease (36 Gy).
Patients in Partial Remission
Interestingly, low-dose IF-RT (20-30 Gy) in patients in par-
tial remission (PR) might be a viable alternative to high-dose
therapy and autologous stem-cell transplantation. In the
Southwest Oncology Group study,34 patients with minimal
and nonminimal residual disease had a 4-year survival rate of
90% and 65%, respectively. The EORTC-GELA29 showed an
87% 5-year OS rate for patients in PR.35
The value of adjuvant radiotherapy in patients in PR has
been acknowledged in the ongoing German Hodgkin Study
Group HD159 study in which PET residual masses (2.5
cm) are treated with adjuvant radiotherapy (30 Gy).
Refractory or Relapsed HL
The role of radiation therapy in these poor prognosis patients
is 2-fold. In patients who are desperately ill, radiotherapy can
improve their quality of life by alleviating symptoms caused
by chemoresistant tumor masses, when high-dose chemo-
therapy and autologous stem-cell transplantation are not
deemed beneficial. Good palliation has been obtained with a
radiation dose of 40 Gy and moderately accelerated radio-
therapy36 or with concomitant chemoradiotherapy.37 The re-
Radiotherapy of HL 211

Figure 3 (A) Orange contouring outlines the initial volume on a prechemotherapy axial CT scan and red outlines the
PET areas. (B) Initial volume superimposed on the postchemotherapy axial CT scan (yellow contouring); blue
outlines the CTV.

ported 1-year local control rates were 73% and 54%, respec- Facts Underpinning the Validity
tively. On the other hand, if more aggressive therapy is of the Chemotherapy-Alone Tenet
warranted, Yahalom and coworkers38 and Poen and cowork- As shown in Table 6, Straus and coworkers45 compared
ers39 showed that IF-RT (15-30 Gy) with or without total the clinical outcome of patients (stage I-III) randomized
lymphoid irradiation (20 Gy) could lead to a 6.5-year dis- between 6 ABVD alone versus 6 ABVD RT (36 Gy IF-RT
ease-free survival of 50% and an improved 3-year FFR rate of or EF-RT). Freedom-from-progression (FFP) and OS were
85%, respectively. In conclusion, the present data suggest similar in both groups (FFP 81% v 86% and OS 90%
that patients can benefit from radiotherapy in such settings. v 97%, respectively). Notwithstanding this undersized
(152 patients) and underpowered study (the sample size
was insufficient to detect a difference of less than 20%),
State-of-the-Art in the Future: some authors43 seized the opportunity to suggest that
ABVD alone could cure a large proportion of patients.
Chemotherapy Alone or However, in a previous study conducted by the Grupo
Response-Adapted Treatment Argentino de Tratamiento de la Leucemia Aguda and
Grupo Latinoamericano de Tratamiento de Hemopatias
Chemotherapy Alone
Rationale
Among the many authors who addressed the issue of late
complications induced by radiation treatments, Leeuwen et
al,7 Travis et al,40 Salloum et al,41 and Bathia et al2 showed a
significantly increased risk of second tumors in patients
treated with radiotherapy alone or combined with chemo-
therapy. Others, namely, Aleman et al,1 Hancock et al,3 and
Ng et al,6 showed an increased risk of cardiovascular compli-
cations. Notwithstanding the fact that these compiled late
complications were because of outdated radiation doses,
fields, and techniques, the proponents of the chemotherapy-
alone concept advocate the total removal of radiation treat-
ments in patients with HL, notably in the case of early-stage
disease.42,43 Interestingly, in a recent review of all random-
ized trials, Franklin and coworkers44 showed that the risk of
second malignancies was not significantly different in pa-
tients with early-stage disease treated with chemotherapy Figure 4 Determination of a CTV in a mediastinal area in CR or CRu
alone or combined-modality treatments. after chemotherapy.
212
Figure 5 (A) Yellow contouring outlines the initial volume on a prechemotherapy axial CT scan. (B) Coregistration of the
prechemotherapy CT scan and FDG-PET. (C) Initial volume (yellow contouring) superimposed on a postchemo-
therapy axial CT scan. (D) Adequate CT contouring on the postchemotherapy CT scan (blue contouring).
Malignas groups,46 significantly better disease-free sur-
vival (DFS) was obtained in patients with early-stage dis-
ease treated with 6 CVPP RT compared with the group
treated with chemotherapy alone. Only in a questionable
subgroup analysis did they find similar results in both
groups. The National Cancer Institute of Canada Clinical
TrialsEastern Cooperative Oncology Group trial47 com-
pared chemotherapy alone (4-6 cycles of ABVD) with a
strategy that included radiation therapy (STNI) in patients
with nonbulky early-stage Hodgkin lymphoma. The
5-year FFP rate was significantly higher in patients treated
with radiotherapy, but OS was similar in both groups. Yet,
because of salvage options and longer survival with disease
in HL, it may take longer follow-up for OS to be influenced
significantly by a high relapse rate. Unfortunately, patients
in most randomized studies have short follow-up. It must
also be emphasized that STNI is an outdated radiation
treatment especially for patients with early-stage disease.
Caveats
It is possible that early-stage disease could be cured with
chemotherapy alone, but there are a number of drawbacks
that may severely affect the quality of life of patients or
lower OS. Firstly, there is a high risk of local recurrence, as
shown by Shahidi and coworkers48 in patients with stage I
and II disease treated with chemotherapy alone (median: 6
cycles, 64% of patients received anthracycline-based che-
motherapy). They reported a 5-year relapse rate of 40%
with 83% of the patients relapsing only at the initially
T. Girinsky and M. Ghalibafian
involved disease sites or at both involved and distant sites.
More recently, the EORTC-GELA H9F trial11 revealed that
after 6 EBVP, patients in CR or CRu in the favorable group
had an unacceptably low FFS rate (70%) when adjuvant
radiotherapy was omitted. Children with early- and late-
stage disease enrolled in the CCG 5942 trial49 fared better,
with a significantly higher 3-year EFS (93% v 85%) when
they received low-dose IF-RT (21 Gy) in complete remis-
sion. Secondly, if combined-modality treatment using
modern radiotherapy (ie, limiting chemotherapy cycles,
radiation doses, and field sizes) is avoided, then a greater
number of chemotherapy cycles will have to be delivered
upfront. This implies potential toxicity because of drug
accumulation. Bleomycin can give rise to pulmonary tox-
icity, and it affected 22% of the patients in the study by
Straus et al.45 Even more distressing, was the fact that
bleomycin-induced pulmonary toxicity50 led to a signifi-
cant decrease (17%) in 5-year OS and the bleomycin-
induced pulmonary toxicity rate (27%) was significantly
higher among patients who had received ABVD. Doxoru-
bicin use entails a significant risk of cardiac toxicity. Doyle
and coworkers51 showed that patients with breast cancer
had a 2.5-fold risk of developing cardiomyopathy if they
were treated with doxorubicin. Aviles and coworkers52
reported a 9% incidence of clinical cardiac events and a
7% mortality rate because of cardiac disease in patients
treated with 6 to 8 ABVD and a median follow-up of 11.5
years. Even more compelling data have recently been re-
Radiotherapy of HL 213

Figure 6 (A) Yellow contouring outlines the initial volume on a prechemotherapy coronal CT scan. (B) Coregistration
of the initial CT scan and FDG-PET. (C) Initial volume (yellow contouring) superimposed on a postchemotherapy
coronal CT scan. (D) Adequate CT contouring (blue contouring) on the poschemotherapy CT scan.

ported by Moser et al53 on behalf of the EORTC group.
Patients treated for aggressive non-HL with at least 6 cy-
cles of doxorubicin-based chemotherapy experienced a
10-year cumulative incidence of cardiovascular disease
(mostly chronic heart failure) attaining 22%. It is notewor-
thy that, in this study, patients who received a radiation
dose of 30 Gy or less did not sustain any increased cardio-
vascular toxicity. These findings support the fact that
small radiation doses given in a combined-modality treat-
ment setting can benefit patients and need not be demon-
ized. Even more interesting is the fact that the combined-
modality treatment concept can help obviate harmful
chemotherapy drugs. Donaldson and coworkers,54 using
low-dose radiotherapy (15-25.5 Gy), showed that patients
could be cured with limited therapy excluding alkylating
agents, bleomycin and etoposide. Landman-Parker and
coworkers55 showed that children with early-stage disease
could be treated with chemotherapy without alkylating
agents and anthracyclines followed by low-dose RT.
Third, patients who develop a recurrence after treatment
with chemotherapy will receive salvage treatment. Patients
receiving salvage therapy are exposed to a much greater
risk of late complications. Moser et al53 showed in a mul-
tivariate Cox regression analysis that salvage treatments
were associated with an increased risk of cardiovascular
disease. In addition, Leeuwen and coworkers,56 Aleman
and coworkers1, and Andre and coworkers57 proved that
patients receiving salvage chemotherapy had a signifi-
cantly increased relative risk of solid cancers. As Yahalom
remarkably concluded,58 combined-modality treatments
should allow us to optimize cure and reduce toxicity in
patients with HL.
The Concept of
Response-Adapted Treatment
Two different concepts underlie the strategy aimed at de-
creasing treatment intensity. The first concept is to de-
crease the intensity of combined-modality treatments in
all patients (as assessed in the randomized study per-
formed by the German Hodgkin Study group HD13); the
number of chemotherapy cycles is reduced, and a combi-
nation of various chemotherapy drugs is tested along with
reduced radiation doses.9 The second concept (response-
adapted treatment) is to customize the treatment intensity
by tailoring the number of chemotherapy cycles and radi-
214
Figure 7 Definition of CTV and GTV for a cervical node in partial remission.
ation doses to each patient.59 Treatment customization
involves defining 3 prerequisites. The first prerequisite is
the response criterion that could be predictive of a favor-
able outcome. The selected criteria in most studies were
complete remission47,54,60-62 or a good response (
70%).55 The second prerequisite is the timing of the eval-
uation of tumor response and its predictive value. In many
studies,47,54,61-63 an early response to therapy (after 2 to 4
cycles of chemotherapy) was predictive of the clinical out-
come. In all studies, prognostic assessment of early re-
sponse was performed in a univariate analysis. However,
Landman and coworkers55 showed that an early response
was not predictive of outcome in a multivariate analysis. It
is, therefore, plausible that we might be able to determine
the required treatment intensity for each individual pa-
tient early during treatment (eg, an additional delivery of
modern miniradiotherapy). In this respect, Meyers find-
ings,47 which showed that FFP was significantly lower in
patients treated with chemotherapy alone and not in CR
after 2 cycles, are relevant. The third prerequisite is find-
ing a reliable way to evaluate tumor response (CT scan or
PET). This issue remains unsolved, but a certain amount of
data is now available. Evaluating tumor response using
FDG-PET after 2 chemotherapy cycles was shown to be
highly predictive of the clinical outcome.64,65 In Hutchings
et als study,64 the PET scan was predictive of outcome
exclusively in patients with advanced-stage disease. Its
predictive value vanished in patients with early-stage dis-
ease given IF-RT after chemotherapy. In Gallamini et als
study,65 the data provided do not allow us to determine
T. Girinsky and M. Ghalibafian
which patients benefited from the predictive value of the
PET scan (over 50% of the patients had advanced-stage
disease). A few randomized studies are currently assessing
the potential predictive value of the PET scan while imple-
menting the response-adapted treatment concept. In the
Manchester trial, as mentioned in Jerusalem and Beguins
article,66 patients with early-stage disease in CR on the PET
scan after 3 cycles of ABVD are randomized between no
further treatment or IF-RT radiotherapy. In the EORTC-
GELA H10 trial, patients randomized in the experimental
arm and in CR (PET negative) after 2 cycles of ABVD will
receive 2 to 4 additional chemotherapy cycles and no ra-
diotherapy. Those with a PET scan will receive an inten-
sive chemotherapy regimen (escalated BEACOPP) and ra-
diotherapy. In the GHSG HD15 trial, patients with
advanced-stage disease and stage IIB with risk factors re-
ceive 8 cycles of chemotherapy. In patients with residual
masses exceeding 2.5 cm, those with a PET scan receive
additional radiotherapy (30 Gy).
New Concepts
and Guidelines for
Radiation Fields in HL
Introduction
As indicated in the previous chapter, chemotherapy alone
is not devoid of serious late complications and second
cancers as follow-up steadily increases.67 On the other
hand, data strongly suggest that the incidence of late com-
Radiotherapy of HL 215

Figure 8 (A) Prechemotherapy axial CT scan. (B) Blue outlines the CTV. (C) Pink outlines the GTV that will receive the
radiation boost. (D) CTV and GTV on the same axial cervical CT scan slice.

plications is partly correlated with the extent of the irra-

diated volume and can be lessened, provided radiation
fields are reduced.4,21,44,68 A reduction in radiotherapy
field sizes (ie, from extended fields to involved fields) did
not translate into any decrease in overall survival accord-
ing to the large meta-analysis reported by Specht and co-
workers.69 Yahalom and Mauch70 defined involved fields
because their delineation was not standardized, and
lymph node regions were often irradiated according to the
Ann Arbor staging diagram, which was not designed to
delimit radiation fields.
A few years ago, the EORTC group began to devise the
concept of involved-node radiotherapy (INRT) in which
only the initial tumor volume (or involved lymph nodes)
would receive radiation, thereby allowing maximal spar-
ing of surrounding normal tissues (notably the heart and Figure 9 Determination of a CTV and a GTV in a mediastinal area in
coronary arteries in case of mediastinal masses). The prin- PR after chemotherapy.
216 T. Girinsky and M. Ghalibafian

Figure 10 (A) Yellow contouring outlines the initial volume on a prechemotherapy axial CT scan. (B) Red outlines
PET areas on the coregistered prechemotherapy CT and FDG-PET. (C) Initial volume superimposed on the
postchemotherapy CT scan. (D) Green outlines the CTV. (E) Pink outlines the GTV which will receive the
additional boost.

ciple was that modern radiotherapy with smaller radiation
fields and sophisticated radiation delivery techniques in a
combined-modality treatment setting, would lower the in-
cidence of late complications significantly. The new INRT
guidelines71 will be applied in the upcoming EORTC-
GELA H10 randomized trial.
Basic Rules for
Implementing the New Guidelines
Patients should have a pre- and postchemotherapy CT and
FDG-PET scan performed in the treatment position. These
scans should encompass cervical, axillary, and mediastinal
areas. Whenever possible, all radiologic data should be
evaluated with the radiologist and the nuclear medicine
physician. FDG-PET will solely be used to pinpoint unde-
tected lymph nodes on CT scan. The remission status
(Cotstwolds criteria) after chemotherapy should be deter-
mined for each initially involved lymph node exclusively
on CT scans.
CR or Cru After Chemotherapy
A clinical target volume (CTV) is contoured on the radio-
therapy planning CT scan. The CTV is the initial volume of
the involved lymph nodes before chemotherapy. It takes
into account the initial location and extent of the disease
(Figs 1 and 2). Normal structures displaced by the en-
larged lymph nodes are not included in the CTV (eg, neck
muscles, Fig 3). Also, whenever possible, blood vessels are
spared if the involved lymph nodes are located at a dis-
tance from them. In case of CRu, the visible lymph node
remnant is included in the CTV. If a mediastinal area is in
CR, the CTV should not exceed the lateral boundaries of
the normal mediastinum to limit lung toxicity. In other
words, the length of the CTV is the length of the medias-
tinal mass (or lymph nodes) before chemotherapy and the
width of the CTV is the width of the mediastinal mass after
chemotherapy (Figs 4-6). Whenever possible (notably
when normal organs were displaced by the initial tumor
masses), large thoracic blood vessels, the origins of the
coronary arteries, and cardiac cavities should be spared
Radiotherapy of HL
Figure 11 (A) Yellow outlines the initial volume on a prechemotherapy coronal CT scan. (B) Initial volume superim-
posed on the postchemotherapy CT scan. (C) Blue outlines the CTV. (D) Pink outlines the GTV which will receive the
additional boost.
(Fig 5). The planning target volume (PTV1) is the CTV
with a margin taking into account organ movement and
setup variations. A 1-cm isotropic margin is usually con-
sidered adequate.
In Case of PR
The gross tumor volume (GTV) is the lymph node remnant
(Figs 7 and 8). The CTV is the initial volume before che-
motherapy, as described earlier, and includes the GTV. If
a mediastinal area is in PR, the lateral borders of the irra-
diated volume should exceed the normal mediastinal
boundaries, but its width should always be that of the
mediastinal mass after chemotherapy (Figs 9-11). Two
PTVs should be defined. PTV1 is the CTV (including the
GTV) with a 1-cm isotropic margin. PTV2 is the GTV with
a 1-cm isotropic margin, and only PTV2 should receive an
additional radiation boost.
Treatment and Dose Prescription
If initially involved lymph nodes are far apart (more than 5
cm), then separate PTVs should be devised; otherwise, they
should be included in the same radiation field.
According to the International Commission on Radia-
217
tion Units and Measurements 50/62,72 the PTV should
receive a dose comprised between 95% and 107%. The
present EORTC-GELA guidelines specify a radiation dose
of 30 Gy to PTV1 and an additional 6 Gy radiation boost to
PTV2.
New Radiation
Delivery Techniques
Rationale
Smaller fields enable more conformal and innovative ap-
proaches to reduce normal tissue exposure and thus mark-
edly lower the risk of late complications.73 This approach
could best be implemented by using the new INRT con-
cept and sophisticated radiation techniques, such as inten-
sity-modulated radiation therapy (IMRT) or respiratory
gating for HL mediastinal masses. This approach should
lower the risk of long-term cardiotoxicity and/or coronary
artery disease. Goodman and coworkers74 showed that, in
such patients, IMRT provided better PTV coverage and
reduced pulmonary toxicity (decreased mean dose to
lungs by 12%-14%) compared with conventional treat-
218
Figure 12 Various virtual volumes designed around the PTV on the axial CT scan slices.
ments or 3-dimensional conformal radiotherapy. IMRT
was also shown to be significantly better in terms of heart
and coronary artery protection compared with conven-
tional treatments or 3D-conformal radiotherapy.75 Two
additional features of IMRT merit consideration. First,
tighter conformal tumor coverage and thus better protec-
tion of nearby organs at risk can be achieved with various
virtual volumes to which selective dose constraints are
assigned (Figs 12-14) (Ghalibafian, unpublished results,
May 2006). Second, IMRT allows radiation oncologists to
deliver larger radiation doses to areas considered at a
higher risk of local recurrence (dose painting). These ar-
eas, which are defined by functional imaging using various
probes to detect either hypoxic or high proliferation areas,
could then be treated with a simultaneous boost. A note of
caution is nevertheless required with IMRT. First, because
IMRT produces tighter conformal doses with a steep-dose
gradient, significant undercoverage of the PTV may occur
in patients whose chest organ movements are neither
monitored nor controlled. This concern was recently ad-
dressed by Duan and coworkers.76 They showed that
IMRT treatments can be affected by respiratory motion
and result in significant dose errors in individual field
doses. However, these errors tended to cancel out between
T. Girinsky and M. Ghalibafian
fields and average out over dose fractionation. The conclu-
sion was that tumors affected by respiratory motion could
be treated with IMRT without significant dosimetric and
biological consequences. Our preliminary results (2-year
EFS and OS of 100%) in 24 patients with HL mediastinal
masses (32% bulky mediastinum) treated upfront with
IMRT (32-40 Gy) after 3 to 6 cycles of ABVD suggest that
IMRT can be safely administered to such patients (Girin-
sky, unpublished results, September 2006). It is notewor-
thy that the use of sophisticated techniques may not be
devoid of pitfalls because of prolonged radiation delivery.
Fowler and coworkers77 suggested that any prolonged
fraction delivery could lead to a possible decrease in the
biological effect. Brincker and Bentzen,78 however,
showed that sensitivity to changes in the dose per fraction
was low in HL. This finding suggests that the capacity to
repair sublethal damage appears to be small, and thus
prolonged radiation delivery should not compromise tu-
mor eradication.
Conclusions
In combined-modality or response-adapted treatment set-
tings, modern radiotherapy will disprove the dystopian views
Radiotherapy of HL 219

Figure 13 Three-dimensional representation of the various virtual volumes

Figure 14 (Right panel) IMRT delivered without dose constraints assigned to virtual volumes. (Left panel) IMRT
delivered with dose constraints assigned to a posterior virtual volume. Better protection of the origins of the coronary
arteries was provided.
220
held by a few medical oncologists. New concepts and new
radiation delivery techniques will ensure better protection of
normal tissues while preserving an excellent clinical outcome
and quality of life.
Acknowledgments
The authors are grateful to Lorna Saint Ange for editing
and to La Ligue Franaise contre Le Cancer, Comit de
Paris and Clarence Westbury Foundation.
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