REVIEW

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Modern radiotherapeutic strategies in

the management of lymphoma

Leslie Ballas*

ABSTRACT The history of radiation therapy in the treatment of malignancies is closely

linked to its use in Hodgkin lymphoma. It was less than a decade after the first publication
on x-rays that radiotherapy was used in the treatment of a Hodgkin lymphoma. Over time,
radiotherapy has evolved with newer technology and better understanding of radiobiology.
During this same time frame, the treatment of Hodgkin and non-Hodgkin lymphomas has
also seen great progress. This review will provide detail on modern radiotherapy techniques,
indications for utilization, and modern radiation field sizes and doses.

Approximately 80,000 patients were diagnosed with lymphoma in 2014: 70,000 patients diag- KEYWORDS 
nosed with non-Hodgkin lymphoma (NHL), while almost 10,000 patients will be diagnosed with • Hodgkin lymphoma
Hodgkin lymphoma (HL). An estimated 20,000 patients will die from lymphoma (the vast majority • involved site
from NHL) in 2014 [1] . Death rates from both Hodgkin and NHL have decreased over the last radiation therapy • ISRT
four decades because of improvements in treatment over time [2,3] . As there are multiple subtypes • non-Hodgkin lymphoma
of lymphoma, survival is dependent on histology and stage of disease [4,5] . • radiation treatment
The development of radiotherapy as a treatment for cancer is closely linked to the historical techniques • radiotherapy
treatment of lymphoma. Radiation therapy was used to treat HL as early as 1902, only 7 years
after the discovery of x-rays by Wilhelm Conrad Rontgen [6] . In 1950, Vera Peters presented the
first definitive proof that patients with early-stage HL could be cured with radiotherapy [6] . With
the development of a linear accelerator at Stanford in the 1950s, Henry Kaplan was able to deliver
larger fields of radiation. Total or subtotal lymphoid irradiation became the standard treatment for
early-stage HL with 5-year survival for localized disease of 72% [7] .
Over time, it was recognized that the large fields of radiation carried significant long-term mor-
bidity including second malignancies, heart disease and thyroid dysfunction. Because of the devel-
opment of effective chemotherapy in the treatment of HL, more extensive fields of radiation were
not necessary to provide curative treatment. Over the past number of decades, radiation treatment
fields have been shrinking. The EORTC H8U, GHSG HD8 and Italian study by Bonadonna et al.
showed the equivalence of involved-field radiation (IFRT) to extended-field RT [8–10] .
Over the past 5–6 years, involved-field radiotherapy has moved from a 2D defined treatment
volume into one that can be more precisely defined in three or four dimensions. The basis for this
type of treatment field derives from the modified involved-field used in pediatric studies [11] as well
as the concept of involved node radiation therapy (INRT) being used by the EORTC/GELA on
protocol.
Radiation oncology has become more sophisticated in its technology and treatment planning
over the last number of decades. As we have learned more about how to treat lymphomas with mul-
timodality therapy through randomized controlled trials, we are now able to offer smaller fields of
radiation to lower doses. These advancements allow us to provide effective and precise treatment.

*Department of Clinical Radiation Oncology, USC Keck School of Medicine, Los Angeles, CA 90033, USA; lballas@med.usc.edu part of

10.2217/FON.14.305 © 2015 Future Medicine Ltd Future Oncol. (2015) 11(6), 1011–1020 ISSN 1479-6694 1011
Review Ballas
Radiotherapy as a component of
multimodality therapy
Today, the use of radiotherapy as the sole treat-
ment modality for lymphoma is only germane to
lymphocyte-predominant HL, early-stage, low-
grade Follicular lymphomas, early-stage MALT
lymphomas, and certain cutaneous lymphomas.
For early-stage HL, combined modality therapy,
regardless of PET-response to chemotherapy, has
been shown on systematic review to improve
tumor control and increase overall survival
(OS) [12] . In patients with advanced-stage HL,
the use of radiotherapy for residual disease after
chemotherapy has proven beneficial [13,14] .
The use of radiation in combination with
R-CHOP chemotherapy in all stages of DLBCL
was shown retrospectively to improve p­rogression
free survival (PFS) and OS [15] .
Immobilization & CT simulation
Patients should have optimal immobilization
for CT simulation. This should include, in
head and neck patients, a thermoplastic mask.
IV contrast should be used, unless there is a con-
traindication, to help delineate vessels and nodal
chains [16] .
Different positioning techniques can be used
to minimize normal tissue within the radiation
field. For example, when treating the mediasti-
num in women, an inclined board can be used
to decrease the volume of breasts and heart in
the radiation treatment field. This technique has
been shown to decrease the dose to breasts and
heart while not compromising dose to the target
in HL patients [17] .
●●Motion management
Radiation accuracy can be limited by organ
motion. If a tumor moves because of normal
organ motion, for example in the lung, it can
move outside of the radiation field. In order
to avoid missing the tumor with the radiation
beam, techniques can be used to take normal
tissue variation into account.
The most common location that motion
affects tumor position is in the chest and abdo-
men due to respiration. In order to account for
this, a 4D CT scan can be used at the time of
simulation. This technique acquires multiple
images at each couch position and correlates
them, via an infrared marker, to the patients’
breathing cycle. Once these images are recon-
structed (after the images are separated into
ten different segments), a 3D rendering of the
1012 Future Oncol. (2015) 11(6)
patients’ anatomy can be used for contouring
the tumor and normal tissues throughout the
breathing cycle.
With motion recorded via 4D CT simulation,
the radiation oncologist can create an internal
target volume (ITV) that delineates where the
tumor is at all points during respiration. This
allows for more conformal treatment since the
patients’ own visualized tumor motion replaces
generic margins that were created to account for
breathing variation (sometimes up to 3 cm). The
increase in the application of conformal treat-
ment reduces the radiation dose received by
n­ormal tissues in the surrounding area.
Respiration can also cause spatial separation
of structures within the mediastinum that can
be used to the patient’s advantage. Deep inspi-
ration has been proven to decrease the amount
of lung exposed to radiation in the treatment
of mediastinal lymphomas by 25% [18,19] . This
spatial separation can further be exploited with
the use of respiratory gating during treatment
delivery. Respiratory gating delivers radiation
only during desired points in the respiratory
cycle. This technique relies on the same infra-
red sensors that are used to generate a 4D CT
simulation. Another technique to maximize the
benefits of inspiration is deep inspiration breath
hold. This requires patients to take a deep breath
and hold it during their treatment. There is a
feedback mechanism for the patients so that they
are able to tell when their breathing/breath hold
is in the treatment range. In order for this treat-
ment modality to be successful, patients must be
capable of holding their breath in a consistent
­manner throughout treatment.
Treatment volumes
The conventional radiation fields used to treat
lymphomas were based on anatomic lymph node
regions defined in the Ann Arbor staging sys-
tem. Because radiation therapy was used as the
sole treatment modality for many decades, large
extended radiation fields were felt to be necessary
to encompass all lymphoid regions. Over time,
as combined modality therapy with multidrug
chemotherapy replaced radiation therapy as a
single modality treatment, it was shown that the
extended fields could be replaced with involved
field radiotherapy at no cost to the patient [9,10] .
Involved field radiotherapy (IFRT) became the
standard of care over the past decade or more [20] .
IFRT restricts radiation to the anatomical nodal
region that was initially involved with disease.
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 Modern radiotherapeutic strategies in the management of lymphoma
As radiation has progressed technologically and
has moved to 3D planning with better delinea-
tion of vasculature and lymphatics, the concept
of involved site radiation therapy (ISRT) has
matured. ISRT radiation fields are modifica-
tions of the involved field, based on pediatric
lymphoma protocols [11] and adult protocols that
use INRT. ISRT is intended to minimize unnec-
essary exposure of normal tissue to radiation and
hopefully prevent some late sequelae of treat-
ment. The rationale for ISRT/INRT is based
on the fact that patterns of relapse after chemo-
therapy alone are usually limited to the initially
involved nodes [21] . In addition, more effective
chemotherapy eradicates microscopic disease,
therefore larger RT fields are not necessary to
eliminate microscopic cells. The widespread
use of better imaging technology for defining
RT targets allows more limited treatment fields.
All of these reasons, coupled with the fact that
late effects of radiotherapy show a direct link-
age between field size and risk of toxicity [22,23] ,
make the use of smaller field sizes essential. The
involved site is based on common radiation def-
initions that delineate p­rechemotherapy gross
disease (see below).
●●Determination of treatment planning
volumes
Modern lymphoma treatment planning should
adhere to the conventions defined by the
International Commission on Radiation Units
and Measurements (ICRU) Report 83. This
includes defining a gross target volume (GTV),
clinical target volume (CTV), planning tumor
volume (PTV) and, if appropriate, as previ-
ously discussed, an internal tumor volume
(ITV). All descriptions below are based on the
International Lymphoma Radiation Oncology
Group (ILROG) guidelines [16] .
●●Presurgery/prechemotherapy GTV
Because lymphomas are very chemosensitive, the
initial prechemotherapy disease is often greatly
diminished by the time radiation is initiated. A
prechemotherapy (or presurgical, when appli-
cable) GTV should be defined based on review
of all of the prechemotherapy imaging. This
v­olume should be included in the CTV.
●●No-chemotherapy/postchemotherapy
GTV
The no-chemotherapy or postchemotherapy
GTV should include the involved nodes (or
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Review
organ) and any residual disease or scar tissue.
This volume is always part of the CTV.
●●Clinical target volume
The clinical target volume (CTV) should
encompass the pretreatment (chemotherapy or
surgery) GTV. The CTV should be edited to
exclude structures that were not involved with
lymphoma initially (e.g., air, muscle, bone,
lungs, kidneys, etc). According to the ILROG,
the following points should be considered in
determining CTV:
●● Quality and accuracy of imaging;
●● Concerns of changes in volume since imaging;
●● Spread patterns of the disease;
●● Potential subclinical involvement;
●● Adjacent organs constraints [16] .
Separate nodal volumes can be encompassed
in the same CTV if they are within 5 cm. If
the involved nodes are more than 5 cm apart,
then the volumes should be treated separately
and should have different PTVs.
●●Internal target volume
The ICRU Report 62 defines an internal tar-
get volume (ITV) as the CTV plus a margin
taking into account uncertainties in size, shape
and position of the CTV within the patient. It
is most commonly used to define a target that
moves within the body. As described previously,
the ITV can be defined at 4D CT simulation.
ITV contours are not necessary in structures that
are unlikely to change position or shape during
treatment (e.g., the neck).
●●Planning target volume
The planning target volume (PTV) expan-
sion will vary somewhat depending on immo-
bilization used, patient cooperation and body
site. PTV takes into account the CTV or ITV
and builds in a margin for setup uncertainty.
Hoskin, et al. on behalf of the Lymphoma
Radiotherpay Group gave general guidelines
based on different body sites treated [24] :
●● Head and neck: 0.5–1 cm depending on local
set-up;
●● Mediastinum: 1 cm transversely and 1.5 cm
cranio-caudally;
●● All other sites: 1 cm.
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Review Ballas
●●Organs at risk
Neighboring normal structures should be con-
toured and dose to these structures should be
analyzed to ensure that structures are kept
within known tissue tolerances based on the
QUANTEC model [25] . The therapeutic ratio
can be evaluated and potential morbidity
a­ssociated with treatment hopefully prevented.
●●Image co-registration
Fluorodeoxyglucose (FDG)-PET is routinely
used for diagnostic purposes in lymphomas.
It has also become increasingly important
for target delineation in radiation therapy.
Hutchings et al. showed that the use of an
FDG-PET scan for contouring purposes could
increase radiation target definitions and the
volume of tissue getting therapeutic dose from
8–87% [26] . The same study also showed that the
use of FDG-PET could decrease the radiation
field [26] . Nodes that require consolidation with
radiation can be missed if a prechemotherapy
FDG-PET is not used in conjunction with CT
images. Girinsky et al. found that FDG-PET
detected lymph nodes that required consolida-
tion with radiation in 36% of the patients that
were undetected by CT [27] .
FDG-PET scans can be co-registered to
treatment planning scans if they are done in
the same position with identical immobilization
(co-registration can be challenging if the initial
FDG-PET was done in a different position from
the treatment position because of anatomic vari-
ation that is associated with arm position/neck
position). FDG-PET simulators have made it
possible to acquire both the treatment planning
CT images and PET images simultaneously.
Without an FDG-PET simulator, the initial
pre-chemotherapy FDG-PET would need to be
performed in the radiation treatment position
with proper immobilization. This is rarely done,
however.
While the most common scenario is to use
FDG-PET to help define tumor volume, MRI,
in the right situations, can be co-registered to
treatment planning CT scans. This is relevant
mostly in disease of the head and neck and
­especially NK/T cell lymphomas.
●●Involved node radiation therapy
INRT was introduced by the European
Association for Research and Treatment of Cancer
(EORTC) for use on protocols of early-stage
HL [28] to replace IFRT. Just as IFRT was initially
1014 Future Oncol. (2015) 11(6)
introduced to shrink radiation treatment fields to
minimize toxicity compared with extended-field
radiation, so too was INRT introduced to limit
the normal tissues exposed to radiation. When
INRT has been compared with IFRT in the
evaluation of normal tissue doses, INRT lead to
a reduction in mean heart dose of 50% and mean
breast dose in 42% [29] .
In both IFRT and INRT, the prechemo-
therapy GTV determines the CTV. INRT
minimizes the treatment fields to the area of the
prechemotherapy involved node with minimal
margin. This technique requires FDG-PET in
the treatment position before administration of
systemic chemotherapy [16] to allow for accurate
image fusion with the CT simulation images.
The contouring process (as described by the
ILROG) is quoted below [16] :
●● The CT images of the prechemotherapy PET/
CT are used to delineate the initially involved
lymphoma volume, the GTVCT as deter-
mined by morphology on CT;
●● The PET images of the prechemotherapy
PET/CT are used to delineate the initially
involved lymphoma volume, the GTVPET as
determined by FDG uptake;
●● The prechemotherapy PET/CT is fused with
the postchemotherapy planning CT scan, the
GTVCT and GTVPET are imported to the
planning CT images;
●● The postchemotherapy tissue volume, which
contained the initially involved lymphoma tis-
sue, is contoured using information from both
prechemotherapy PET and prechemotherapy
CT, taking into account tumor shrinkage and
other anatomic changes. The CTV encom-
passes all of the initial lymphoma volume
while still respecting normal structures that
were never involved by lymphoma, such as
lungs, chest wall, muscles and mediastinal
normal structures.
The expansion to PTV is similar to ISRT
and depends on immobilization and site under
treatment.
●●RT as the sole modality of treatment in
lymphocyte predominant HL or localized
indolent NHL
When RT is not combined with chemotherapy
in the definitive management of either lympho-
cyte predominant HL (LPHL) or indolent NHL,
the CTV needs to encompass any suspected
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 Modern radiotherapeutic strategies in the management of lymphoma
subclinical disease. This would involve the GTV
plus any adjacent lymph nodes in that site with
a generous margin.
Treatment techniques
In deciding which treatment technique to use,
the radiation oncologist must weigh giving more
normal tissue full radiation dose (as is com-
monly the case in AP-PA plans) against giving
larger volumes of normal tissue lower radiation
dose (which is commonly the case with IMRT
and volume arc treatments).
●●Intensity-modulated radiation therapy &
volumetric modulated arc therapy
Intensity-modulated radiation therapy (IMRT)
refers to radiation delivery via multiple small
‘beamlets’ of varying intensities to precisely
radiate a tumor. The radiation intensity of
each beamlet is controlled, and the shape of
the beam changes throughout treatment. This
advanced technology allows for more confor-
mal treatment and better avoidance of sur-
rounding structures. This can be particularly
important in mediastinal treatment in which
IMRT provides better protection of the heart
and coronary arteries [16] .
Volumetric-modulated arc therapy (VMAT)
delivers radiation with varying intensity
through beamlets of varying shape as well.
Its distinguishing feature from IMRT is that
it delivers continuous treatment through one
or more arcs. This form of treatment decreases
treatment time significantly. When comparing
treatment plans, VMAT offered no significant
advantages over conventional IMRT for IFRT
plans. It also produced equal dose homogene-
ity to the target. For ISRT/INRT planning,
however, VMAT dose to the lung, thyroid and
breast were lower [29] .
Both IMRT and VMAT cause larger volumes
of normal tissue to be exposed to low dose radia-
tion while three-dimensional conformal radia-
tion delivers prescription dose to larger volumes
of normal tissue. Because of the highly confor-
mal treatment, it is essential to give enough mar-
gin to account for tissue movement so as not to
cause geographic miss of the tumor. 4DCT sim-
ulation is especially important in these settings.
●●Proton therapy
Proton radiation diminishes the dose of radia-
tion deposited in tissue outside the target
(the integral dose) by taking advantage of the
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Review
physical properties of protons. In a comparison
of 3D conformal RT (3DCRT), IMRT and
proton therapy, proton therapy decreases inte-
gral dose over both 3DCRT and IMRT. This
was specifically seen as decreased dose to the
heart, lungs and female breasts. Of the three,
the IMRT plan had the most conformal high-
dose distribution [30] . While a Phase II study has
shown excellent outcomes at 37 months follow-
ing proton INRT, decades of data are necessary
to determine if these reductions in integral dose
make a difference in long-term sequelae [30] .
Patient selection for radiation
●●Response-adapted selection
Response-adapted selection of patients for
radiation therapy, or selection of patients who
can omit radiotherapy as part of their treat-
ment paradigm, is an area of investigation both
in the pediatric and adult population. The
Children’s Oncology Group (COG) recently
completed AHOD 0031 that randomized
patients to RT or no further therapy based on
their early response to two cycles of ABVE-PC
chemotherapy. Those with a >60% reduction
in the prechemotherapy lymphoma mass on
CT scan after two cycles of chemotherapy and
a subsequent complete response (CR) to four
cycles were randomized to either 21 Gy IFRT
or no RT. The 3-year disease-free survival rates
showed no statistically significant difference in
treatment arms [7,31] . AHOD0431, a low-risk
study, omitted RT based on radiologic response
to three cycles of ABVE-PC. AHOD0431 was
closed to accrual because of an unexpectedly
high relapse rate in the non-RT arm [7,32] .
In the adult population, the question of omit-
ting RT based on PET response was studied in
the EORTC/GELA H10. H10 randomized
stage I/II HL patients to RT or no further
therapy in patients who were PET negative
after two cycles of ABVD chemotherapy. H10
found that chemotherapy alone did not produce
equivalent disease-free survival compared with
the combined modality arm. Because of this, the
non-RT arms of the study were closed early [7] .
HD16 and HD17 are currently accruing patients
to similarly designed studies.
Picardi et al. looked at whether RT could be
eliminated in patients with bulky stage I–IV
patients treated with six cycles of VEBEP, if a
CR (PET negative with >75% reduction in CT
detected mass) was achieved. What they found
was that in the non-RT arm, the event-free
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Review Ballas
survival (EFS) was only 86% at 40 months,
despite PET CR. There were fewer relapse
events in the RT arm [33] . The combined expe-
rience of the pediatric and adult cooperative
studies shows that response-adapted therapy is
not standard of care and should be utilized only
on a clinical trial.
Dose: HL
●●Classical HL
Over the past couple of decades, radiation dose,
as well as field size, has been studied in order to
minimize treatment related effects in the long
term. Dose de-escalation has been at the forefront
of both the German Hodgkin Study Groups and
the EORTC in both the favorable and unfavora-
ble early-stage Hodgkin population. Studies have
examined 20 Gy versus 36 Gy or 40 Gy with
different chemotherapeutic regimens [34,35] .
Most recently HD10 (early-stage favorable
patients) and HD11 (early-stage unfavorable
patients), both using a 2 × 2 design, randomized
patients with classical HL to either 20 Gy IFRT
or 30 Gy IFRT. In HD10, stage I/II favorable
patients showed no difference in overall sur-
vival or progression-free survival to two cycles of
ABVD followed by either 20 Gy or 30 Gy [36] .
HD11 studied 20 Gy versus 30 Gy IFRT in the
stage I/II unfavorable patients and found that if
the patient receives four cycles of BEACOPP that
20 Gy is equivalent to 30 Gy in terms of freedom
from treatment failure, progression-free survival
and overall survival [37] . If the patient receives
four cycles of ABVD, however, the patient must
receive 30 Gy as consolidation. Four cycles of
ABVD and 20 Gy is inferior and not recom-
mended. Based on these findings, the current rec-
ommendation, if patients meet the HD10 criteria,
is to use 20 Gy IFRT after two cycles of ABVD. If
patients have early unfavorable disease and meet
the HD11 study criteria, the r­ecommendation is
for 30 Gy to follow four cycles of ABVD.
●●Lymphocyte predominant HL
The use of RT alone in the curative manage-
ment of lymphocyte predominant HL (LPHL)
has been used for decades. In a multicenter retro-
spective study examining the treatment of LPHL
with definitive radiation showed that doses of
30–36 Gy are sufficient [38] .
●●Refractory & recurrent HL
Patients who have residual lymphoma after chem-
otherapy may be considered for 36–40 Gy to the
1016 Future Oncol. (2015) 11(6)
CTV. Patients with refractory disease should be
discussed in a multidisciplinary setting to deter-
mine what salvage options are best suited for the
patient.
Dose: NHL
●●Indolent NHL
A prospective randomized Phase III trial com-
paring 40–45 versus 24 Gy for stage I/II local-
ized-early stage disease was undertaken in the
UK. They reported that with a median follow-
up of 5.6 years, there was no difference in the
overall response rate (ORR) between standard
and lower-dose arms [39] . Because indolent lym-
phomas are exquisitely sensitive to radiation
responding to doses of 4 Gy, further dose de-
escalation in the curative setting was explored
in a randomized Phase III study. This study, by
Hoskin et al., randomized patients with indolent
lymphomas to 4 versus 24 Gy treatment. The
results showed that there was increased local
progression and shorter duration to progression
in the 4 Gy arm compared with the 24 Gy arm
of the trial [40] .
In advanced stage indolent lymphomas, radia-
tion can be used for palliation of symptomatic
disease. In these patients, a low dose of 4 Gy in
two fractions achieves overall response rates of
>80% [41] . While the Hoskin randomized control
trial found that 24 Gy yields better results than
4 Gy in the palliative setting, it is reasonable to tai-
lor the dose based on the clinical scenario (dissemi-
nated disease, etc.) to assess whether the modest
decrease in local control with 4 Gy is tolerable [40] .
●●Aggressive NHL
The Lowry UK study also randomized patients
with aggressive NHL (predominantly DLBCL) to
40–45 versus 30 Gy consolidative radiation (most
patients had received prior chemotherapy) and
found that with the same 5.6 years of follow-up,
there was no significant difference in the overall
response rate or the OS rate between the two dose
levels. There was also a trend for reduced toxicity
in the low-dose arm [39] . Because the majority of
the patients included in the study were DLBCL,
it is worth mentioning that certain aggressive
lymphomas may require higher doses; one such
example is natural killer T cell lymphomas, which
require doses of at least 50 Gy [42] .
●●Refractory & recurrent NHL
This patient population needs discussion at a mul-
tidisciplinary tumor board to decide on the best
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 Modern radiotherapeutic strategies in the management of lymphoma Review

EXECUTIVE SUMMARY
Radiotherapy as a component of multimodality therapy
●● Radiotherapy is rarely used as the sole treatment modality in Hodgkin lymphoma (HL) or non-HL (NHL), it is more
commonly used as part of combined modality therapy with chemotherapy.
Immobilization & CT simulation
●● Optimal immobilization and positioning techniques allows for more conformal treatment that can help minimize dose
to organs at risk.
●● Motion management:
ūū Tumor motion that is attributable to normal organ variability (such as the lungs during respiration) should be
accounted for with the use of specialized techniques at the time of CT simulation (4DCT, deep inspiration breath
hold) and during treatment.
Treatment volumes
●● Determination of treatment planning volumes:
ūū With the widespread use of 3D imaging for radiation planning, treatment planning volumes should be contoured
and defined.
●● Presurgery/prechemotherapy gross tumor volume:
ūū Because lymphomas are chemosensitive and the postchemotherapy residual will vary quite a bit from the
prechemotherapy gross tumor volume (GTV), the prechemotherapy volume should be defined because it will
need to be included in the clinical target volume (CTV).
●● No chemotherapy/postchemotherapy GTV:
ūū This volume should include any residual disease.
●● CTV:
ūū The CTV is dependent on quality and accuracy of imaging, spread patterns of disease and potential subclinical
involvement. It should be edited to exclude structures that were not involved with lymphoma initially.
●● Internal target volume:
ūū The internal target volume (ITV) takes into account uncertainties in size, shape and position of the CTV by adding a
margin onto the CTV based on tumor position variability.
●● Planning target volume:
ūū Planning target volume (PTV) accounts for interfraction variability by adding a margin onto the CTV/ITV based on
immobilization and local set-up.
●● Organs at risk:
ūū QUANTEC has developed recommendations for normal tissue tolerances; these recommendations are in place to
help avoid morbidity and mortality that can be associated with treatment.
●● Image co-registration:
ūū FDG-PET co registration can help define contours. MRI co-registration can also be helpful in defining treatment
volumes in the brain and possibly the head and neck.
●● Involved node radiotherapy:
ūū Involved node radiotherapy (INRT) describes a smaller field of radiation that is currently under investigation by the
EORTC-Gela and should be used on protocol until results of that randomized trial are available.
●● RT as the sole modality of treatment:
ūū When RT is used as the sole modality of treatment, treatment planning volumes may require larger margins.

future science group www.futuremedicine.com 1017

Review Ballas

EXECUTIVE SUMMARY (CONT.)

Treatment techniques
●● Intensity-modulated radiation therapy and volumetric-modulated arc therapy:
ūū Intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques are
described. Both techniques allow for highly conformal treatment while exposing larger volumes of normal tissue
to low dose radiation.
●● Proton therapy:
ūū The benefits of proton radiation in the setting of lymphomas are starting to be explored. The theoretical benefit of
lower doses to surrounding normal tissues exists, but we do not have long-term data yet to show if that translates
into clinically meaningful end points.
Patient selection for radiation
●● Response-adapted selection:
ūū Omitting radiation based on FDG-PET response has been studied in the pediatric and adult population. Based on
the EORTC/GELA H10, there is no data to show that RT can be omitted in stage I/II HL based on FDG-PET response.
Dose: HL
●● Classical HL:
ūū HD10 and HD11 showed that lower doses of radiation could be used with fewer cycles of chemotherapy in the
early favorable stage I/II patient population. This same decreased dose cannot be used in early unfavorable
patients.
●● Lymphocyte predominant HL:
ūū Lymphocyte predominant HL (LPHL) is a situation in which RT can be used as the sole treatment modality. Doses of
30–36 Gy have proven sufficient.
●● Refractory and recurrent HL:
ūū Higher doses of radiation therapy are necessary in recurrent or refractory disease.
Dose: non-HL
●● Indolent non-HL:
ūū A randomized Phase III trial from the UK showed that lower doses of radiation could be safely and effectively used
in indolent NHL.
●● Aggressive NHL:
ūū The same Phase III trial from the UK proved that doses of 30 Gy was sufficient in consolidation of aggressive
lymphomas following chemotherapy.
●● Refractory and recurrent NHL:
ūū Higher doses of radiation therapy are necessary to treat refractory or recurrent NHL.

salvage option. Often, these patients are candidates Conclusion

for stem cell transplantation (SCT). Radiation
may be a component of the salvage protocol to
sites of dominant disease or sites of recurrence. In
patients who achieve a CR to salvage chemother-
apy, 30–40 Gy prior to or after transplantation can
be utilized for maximal local control. In patients
who are not candidates for SCT, radiation doses
of up to 55 Gy may be necessary [43] .
Modern radiotherapy in the management
of lymphomas is a complex and individual-
ized treatment option for many patients. The
advances are the result of multiple randomized
clinical trials that have been aimed at maintain-
ing excellent cure rates while minimizing treat-
ment related side effects. As part of that goal,
there has been a decrease in both radiation fields

1018 Future Oncol. (2015) 11(6) future science group

 Modern radiotherapeutic strategies in the management of lymphoma Review

and doses. Hopefully, as we move forward, we
will see these modifications improve late effects
from treatment.
Future perspective
Over the next 5–10 years, as medicine con-
tinues to evolve, the treatment of lymphomas
will likely involve more immune-modulated
treatments. We have seen tremendous progress
with monoclonal antibodies and other immune
checkpoint drugs in clinical trials. As the field
of immunotherapy continues to expand, the
role radiation plays will likely evolve with it.
In melanoma treatment, there has been great
interest in the abscopal effect (the use of local-
ized treatment not only shrinking the treated
tumor but also eliciting a response in tumors
outside the treatment field). It will be interest-
ing to see if this can be harnessed in the treat-
ment of lymphomas to treat what is often times
a systemic disease.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involve-
ment with any organization or entity with a financial inter-
est in or financial conflict with the subject matter or materi-
als discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or p­ending, or
royalties.
No writing assistance was utilized in the production of
this manuscript.

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