C HA P T E R 95

PRINCIPLES OF RADIATION THERAPY FOR HEMATOLOGIC

DISEASE
Idalid Franco, Daphne Haas-Kogan, and Andrea K. Ng

The approach and utilization of radiation therapy (RT) for the treat- (IFRT), which included only involved nodal regions. However, similar
ment of hematologic malignancies have seen many changes through- to EFRT, IFRT still relied on 2D planning using bony landmarks to
out the years. Advances in imaging and technology have allowed for set field borders, with largely anterior-posterior beam arrangements,
more precise delineation and targeting of disease. This, along with resulting in unnecessary exposure of a large amount of normal tis-
a reduction in radiation doses and treatment volume, have resulted sue. Involved-site radiation therapy (ISRT), the current standard
in increased sparing of normal tissues and dramatically reduced treatment field, uses 3D-based simulation to incorporate the pre-
short- and long-term toxicities previously associated with RT. With chemotherapy volume into the clinical target volume, while exclud-
the majority of hematologic malignancies being highly responsive ing uninvolved areas and previously displaced organs based on tumor
to radiation, RT plays a critical role in disease management. Use of response. Involved-node radiation therapy (INRT), is a special case of
RT ranges from definitive primary treatment to adjuvant therapy in ISRT where staging imaging is acquired with the patient in the RT
combination with systemic therapies, as well as salvage or palliative position, using the same breathing instructions and immobilization
therapy in the relapsed/refractory setting. This chapter will detail the devices. This typically results in further reduction in the irradiated vol-
historical changes in the application of RT for hematologic malig- ume by allowing more accurate target delineation. Pictorial representa-
nancies and focus on the current role of RT based on modern stag- tions of the changes in HL treatment fields over the years are useful in
ing, systemic therapies, response assessment, and RT delivery. We visualizing the substantial changes that RT has encountered over the
will provide current recommendations based on clinical evidence years (Fig. 95.1). Detailed guidelines on ISRT/INRT approaches for
and published guidelines. The goal is to equip the hematologist and HL have been published and recently updated by the International
oncologist with an evidence-based approach to understanding the Lymphoma Radiation Oncology Group (ILROG), available at https://
overall role and clinical applications, including new concepts in mod- www.ilrog.org/main-st. A Mini-Atlas of case examples, focusing on the
ern RT for a wide variety of hematologic malignancies. technical aspect of RT, has also recently been published by the group.2

HISTORY AND BACKGROUND MODERN RADIATION PLANNING AND TREATMENT

Technological advances that are associated with the diagnosis, treat- TECHNIQUES
ment response evaluation, and delivery of RT in the last several decades
have allowed for more precise and personalized treatment applications There have been significant technological advances since the days of
for patients. Even within the last 30 years, advances in the components 2D planning and predominantly anterior-posterior beam arrange-
of RT delivery have allowed for higher precision in dose composition. ments to large treatment fields. With the advent of 3D planning,
The use of more advanced imaging acquisition for staging and planning advanced radiation planning and treatment delivery including inten-
has allowed for better patient selection and smaller treatment volumes, sity-modulated radiation therapy (IMRT), proton beam therapy,
resulting in high rates of long-term tumor control with reduced normal image-guided radiation therapy (IGRT), and motion management
tissue exposure and the associated short- and long-term complications. techniques, highly conformal treatment with significant sparing of
The use of combined systemic treatments with RT, including chemo- normal tissue can be achieved while maintaining disease control.
therapy and more recent targeted and immunotherapy, have resulted in IMRT improves conformality of radiation dose to target structures,
improved locoregional control and overall survival (OS). This chapter while limiting doses to surrounding normal tissues by using multiple
aims to provide a framework through which the image of radiation will beams of varying intensities and shapes that change throughout the
shift from a one-size-fits-all, to the individualized targeted therapy that treatment to precisely irradiate a target. For mediastinal cases, the use
is currently used in most radiation oncology practices. of deep-inspiration breath-hold technique displaces the lungs and
heart away from the radiation fields and has been shown to result in
significantly reduced lung and heart doses. IGRT via daily cone-beam
Hodgkin Lymphoma and the Changing Landscape CT imaging results in further reduced doses to critical structures by
allowing a narrower expansion of the clinical target volume to plan-
In 1950, Vera Peters was the first physician to definitively show that ning target volume. More recently, the use of a Magnetic Resonance
RT could be used to cure early-stage Hodgkin lymphoma (HL).1 Until Linear Accelerator (MR Linac), with its better image quality, its use
that time, HL was thought to be incurable. Dr. Peters not only showed of non-ionizing radiation, and its ability to adapt the daily radiation
that high doses of fractionated RT resulted in a 5- and 10-year survival as tumor responds, has the potential to further reduce RT volume
rate of 88% and 79%, but also proposed the importance of a staging and normal tissue exposure. For proton-beam therapy, its dose profile
system in prognosis. Historically, RT alone was used to treat early- with a sharper fall off can decrease unwanted dose to critical cardiac
stage HL, through the use of 2D imaging set up to bony landmarks. structures. Guidelines on the use of proton therapy for mediastinal
Extended-field radiation therapy (EFRT) included total nodal irradia- lymphoma have been published by ILROG. Ultimately, it is criti-
tion (TNI), mantle and paraaortic/splenic RT, mantle field RT, and cal that these various advanced radiation treatment approaches be
inverted-Y field RT. These large-field treatments were associated with adapted to provide the greatest benefit by accounting for patient char-
significant long-term toxicities, including risks of second malignancy acteristic, needs, and treatment goals.
and cardiac diseases. In the 1990s, in the context of combined modal- Numerous dosimetric and modeling studies have estimated and
ity therapy, EFRT was replaced by involved-field radiation therapy quantified the reduction in doses to normal organs, including heart,

1583
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 1584 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

TNI STNI IFRT INRT

Mantle

Para aortìc
and spleen

Pelvic

2D 3D PET-CT fusion
Breath-hold
IMRT
Proton
IGRT

40–44 Gy 20–36 Gy
Figure 95.1 HISTORICAL EVOLUTION OF TREATMENT FIELDS IN HODGKIN LYMPHOMA. IFRT, Involved field radiation therapy; IGRT,
image guided radiation therapy; IMRT, intensity modulated radiation therapy; INRT, involved node radiation therapy; PET-CT fusion, positron emission tomog-
raphy with correlative anatomic information from computed tomography; STNI, subtotal nodal irradiation; TNI, total nodal irradiation.

lung, and breasts, using modern fields, doses, and techniques. Fig. pre-treatment, [18 F]-fluorodeoxyglucose (FDG) positron emis-
95.2 is an example of a modeling study showing significantly reduced sion tomography-computed tomography (PET/CT) is best practice
estimated breast cancer, lung cancer, and cardiovascular mortality for not only staging but also for RT planning and assessment of
risks when comparing the historical mantle field with more limited response to systemic treatment. Magnetic resonance imaging (MRI)
radiation fields and modern radiation technology.3 There is a growing is recommended in tumors of the central nervous system (CNS),
effort to track volumetric dose estimates to critical normal organs, head and neck (orbits, paranasal sinuses, and skull base), and skel-
including cardiac substructures such as left anterior descending artery, etal sites to determine and distinguish disease from inflammatory
heart valves, and cardiac chambers. This will facilitate work on corre- response. Thin CT slices (2 to 3 mm) with IV contrast are also rec-
lating dose-volume exposure of normal organs with late effects, which ommended for treatment planning CT to assist in nodal and soft-
in turn will guide future treatment and follow-up. tissue target delineation. IGRT for verification of accurate delivery
of planned dose allows for smaller volume expansion and steeper
dose gradients and is recommended for sites where critical organs at
Optimal Use of Imaging risk are in close proximity to the planning target volume, including
mediastinum and head and neck regions. Adaptive IGRT with real
Guidance on optimal use of modern imaging techniques in the time shifts are used when there are large changes anticipated in the
staging, planning, treatment delivery, and follow-up of hemato- anatomy or when small changes will result in significant impact on
logic malignancies was recently published by ILROG. A baseline dose distribution.

Risk Estimates 3D-CRT VMAT Proton Mantle

Breast Ca 3.7% 8.0% 1.4% 23%

Lung Ca 4.4% 6.0% 3.3% 10.5%

CV Mortality 1% 1.1% 0.9% 2.9%

Figure 95.2 MODELING OF DATA ON LATE EFFECT RISKS TO ORGANS AT RISK WITH THE USE OF MODERN RADIOTHERAPY
TECHNIQUES. CRT, Conformal radiation therapy; PT, proton therapy;VMAT, volumetric modulated arc therapy. (Adapted from Maraldo MV, Brodin NP,
Aznar MC, et al. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann
Oncol. 2013;24[8]:2113–2118.)

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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1585

RADIATION THERAPY BY DIAGNOSIS ABVD. For patients with favorable prognosis disease who achieved
early complete PET response to ABVD, the 5-year PFS of the com-
Hodgkin Lymphoma bined modality therapy arm was significantly higher than that of
the chemotherapy alone arm (99%, vs. 87.1%). For patients with
HL may present as limited or advanced-stage disease.4 Limited stage unfavorable prognosis disease, the corresponding 5-year PFS of the
is typically further categorized into favorable and unfavorable prog- two arms were 92.1% and 89.6%, respectively. The difference was
nostic groups. Table 95.1 summarizes the definition of favorable- not significant but the pre-specified, non-inferiority margin was not
prognosis disease, according to the German Hodgkin Study Group met; hence, non-inferiority of chemotherapy alone could not be con-
(GHSG) and European Organization for Research and Treatment of cluded.9 For patients with interim PET-positive disease, compared
Cancer (EORTC) (see the box with Case 1). to the standard arm of ABVD followed by INRT, the 5-year PFS of
Table 95.2 summarizes the results of the GHSG HD10 and intensifying therapy to dose-escalated BEACOPP or BEACOPP-14
HD11 trials, conducted prior to the incorporation of FDG-PET in followed by INRT was significantly higher (90.6% vs. 77.8%).
guiding treatment decisions.5 These two trials evaluated treatment However, escalating treatment to BEACOPP was associated with
de-escalation for early-stage, low-risk, and high-risk patients, respec- significantly higher rates of grade 3 and 4 hematologic toxicities.
tively. The GHSG HD10 compared 4 versus 2 cycles of adriamy- The GHSG HD16 trial randomized limited-stage, low-risk HL to
cin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by 2 cycles of ABVD followed by 20 Gy IFRT, versus the PET-guided
30 versus 20 Gy IFRT. At a median follow-up of 98 months, no treatment arm of 2 cycles of ABVD, with omission of RT if PET
differences occurred in freedom from treatment failure (FFTF) and negativity was attained after chemotherapy. At a median follow-up
OS among the four arms, leading to a recommendation of 20 Gy time of 45 months, among patients with PET-negative scan at the
after 2 cycles of ABVD in patients with limited stage, low-risk HL.6 end of chemotherapy, 5-year PFS was 93.4% for the RT arm and
The GHSG HD11 trial compared 4 cycles of ABVD versus 4 cycles 86.1% for the non-RT arm, leading to the conclusion, similar to
of baseline bleomycin, etoposide, doxorubicin, cyclophosphamide, the RAPID and EORTC/LYSA/FIL H10 trials, that RT cannot be
vincristine, procarbazine, and prednisone (baseline BEACOPP), fol- safely eliminated despite complete PET response to ABVD chemo-
lowed by 20 Gy versus 30 Gy of IFRT. At a median follow-up of therapy.10 The GHSG HD17 trial randomized limited-stage, high-
106 months, there were no differences in outcome between 20 Gy risk HL patients to 2 cycles of escalated BEACOPP and 2 cycles of
versus 30 Gy after BEACOPP, but inferiority of 20 Gy after 4 cycles ABVD, followed by 30 Gy IFRT, versus the PET-guided treatment
of ABVD could not be excluded. A radiation dose of 30 Gy therefore arm of the same chemotherapy, with omission of RT if PET nega-
remains the standard in limited stage, unfavorable HL, after ABVD tive after the chemotherapy and 30 Gy INRT if PET positive. At a
chemotherapy.7 median follow-up time of 46 months, the 5-year PFS of the standard
More recent trials have explored using PET-guided response to arm of combined modality therapy was 97.3% versus 95.1% in the
chemotherapy to further de-escalate or escalate therapy. Table 95.3 PET-directed therapy arm, demonstrating non-inferiority for the
summarizes results of these trials, focusing on the elimination of RT, PET-stratified treatment approach. This is the first randomized trial
based on PET-guided response or early PET-response to chemother- in early-stage HL that showed that RT can be eliminated if complete
apy. The RAPID trial compared combined modality therapy with response to chemotherapy, though the chemotherapy that was used
chemotherapy alone in stage I-IIA non-bulky patients with complete included escalated BEACOPP, which is not a commonly used regi-
PET-response (Deauville 1–2) after 3 cycles of ABVD.8 At a median men, especially among early-stage patients in the United States. Of
follow-up time of 60 months, by intent-to-treat analysis, the 3-year, note, the GHSG HD17 is also the first study comparing INRT with
progression-free survival (PFS) rate was 94.6% in the RT group and IFRT in a prospective randomized fashion.11
90.8% in the non-RT group (P = .16). Although the difference was The role of RT for patients with advanced-stage HL is less well
not statistically significant, the pre-specified, non-inferiority margin defined. The GHSG HD12 trial is a four-arm study for patients
of 7% points was not met and hence, non-inferiority of chemo- with bulky-stage IIB and stages III-IV disease, comparing two dif-
therapy alone could not be concluded. Moreover, by per-protocol ferent BEACOPP variants with or without RT. Among the patients
analysis, after excluding patients who were randomized to the RT with initial bulky disease (>5 cm) or residual disease after chemo-
arm but did not receive the treatment, there was a significant differ- therapy (>1.5 cm), patients randomized to the non-RT arm had
ence between the arms in favor of RT (3-year PFS 97.1% vs. 90.8%, a significantly inferior 10-year PFS in comparison to patients on
P = .02). The EORTC/LYSA/FIL H10 trial examined adapting the RT arm (83.5% vs. 88.6%). In the subgroup of patients with
therapy in early-stage patients, according to early PET response to residual disease (>1.5 cm), patients on the non-RT arm had both
a significantly inferior PFS (83.4% vs. 89.7%) and OS (88.4% vs.
94.4%). Using PET-guided response to chemotherapy for RT deci-
sion in advanced HL was addressed in several trials. In the GHSG
TABLE Limited Stage Hodgkin Lymphoma, Definition of HD15 trial, after dose-escalated BEACOPP and its variants, RT was
95.1 “Favorable-Prognosis” Disease According to limited to patients with residual disease of 2.5 cm and with residual
the German Hodgkin Study Group and European PET avidity. The 4-year PFS in patients with complete response
Organization for Research and Treatment of Cancer or those with PET-negative disease/partial response, after chemo-
GHSG EORTC therapy and non-RT, were 92.6% and 92.1%, respectively, showing
that in patients with complete metabolic response to BEACOPP,
Age — <50 excellent results can be achieved without RT. In the GITIL/FIL
Histology — — HD 0607 trial, patients with a negative PET scan after 2 cycles of
Erythrocyte <30 or <30 or ABVD continued on to a total of 6 cycles of ABVD; those with a
Sedimentation Rate large nodal mass at diagnosis (≥ 5 cm), who continued to be PET-
<50 with no B <50 with no B
(ESR)/B Symptoms negative, were randomly assigned to RT or no further treatment. At
Symptoms Symptoms
a median follow-up of 3.6 years, there was no difference in 3-year
Large Mediastinal No No PFS between the two arms (97% vs. 93%; P = .29). When the anal-
Adenopathy (LMA) ysis was limited to the subgroup of patients with large nodal mass
Extranodal Lesions None — of greater than 10 cm, the 3-year PFS rates were 94% versus 86%
(P = .34), although the comparison in this subgroup may be limited
Number of Sites <3 <4
by inadequate power. Routine addition of RT, after chemotherapy,
EORTC, European Organization for Research and Treatment of Cancer; GHSG,
in patients with advanced-stage HL is not supported by available
German Hodgkin Study Group. data but should be considered in patients who lack complete meta-
bolic response to modern chemotherapy.

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 1586 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

CASE 1
A 28-year-old female with classic Hodgkin lymphoma with Deauville 4
response to chemotherapy:

The patient received involved site radiation therapy (ISRT) to 30 Gy (in

1.5 Gy per fraction, CTV_30 contoured in red) with simultaneous inte-
grated boost to residual fluorodeoxyglucose avid site to 40 Gy (in 2 Gy
per fraction, CTV_40 contoured in green). Patient was planned in arms
down position on 10-degree incline board to displace breast tissue infe-
riorly. Intensity modulated radiation therapy (IMRT) with butterfly tech-
nique was used (limiting arcs to narrow angles anteriorly and posteriorly
to reduce low-dose bath to breasts and lungs):

Continued

Nodular Lymphocyte Predominant Hodgkin Lymphoma Relapsed/Refractory Hodgkin Lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) ILROG guidelines outlined key indications for incorporating peri-
is rare, accounting for only 5% of all HL cases, half of which pres- transplantation RT, including localized sites of relapsed/refractory
ent at an early stage. In these early, localized, stage I, or contiguous disease, bulky disease, incomplete response to salvage therapy, and
stage II cases, ISRT may be preferred single-modality treatment. involvement of sites where local control is critical. Specific emer-
Although the rarity of the disease limits prospective randomized gent situations, secondary to disease progression, include spinal cord
data to guide treatment, large-database studies have shown excellent compression and superior vena cava syndrome. Depending on the
outcome with the use of RT. A recent large multi-center study, con- response to salvage therapy, doses of 30 to 40 Gy are recommended.
ducted by ILROG, showed a 5-year PFS rate of 91.1% for stage I–II A frequently used strategy is to treat responsive disease sites to 30 Gy
NLPHL treated with RT. Treatment should focus on treating the and boosting partially responding sites to 36 to 40 Gy. The target
entirety of the disease, while limiting unnecessary exposure of nor- volume should be determined on a case-by-case basis, depending on
mal tissues. ILROG guidelines are available and recommend a gen- disease location and distribution, but at a minimum should include
erous clinical target volume to encompass microscopic subclinical the site(s) of relapsed/refractory disease, and if feasible, should
disease and a gross tumor volume (GTV) that is readily visualized. include adjacent and previously involved sites. Many systemic agents
Typical dosing is 30 to 36 Gy in 15 to 18 fractions. Additionally, used in HL, either in the upfront or salvage setting, are associated
biopsy confirmation of relapsed disease is strongly advised to rule with increased pulmonary toxicity, including bleomycin, carmustine,
out transformed lymphoma. brentuximab, and immune checkpoint inhibitors. Close attention to

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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1587

CASE 1—CONT’D
Dose-volume histogram showing doses to organs-at-risk (OAR), and summary table comparing mean doses to OAR with this current ISRT, compared
to the typical mean doses to the same OAR in a historical mantle field:

Relative dose [%]

0 25 50 75 100
100

80
Ratio of Total Structure Volume [%]

60

Thyroid

40 LAD
Lungs Heart
LV

L breast,
20 R breast

0
0 1000 2000 3000 4000
Dose [cGy]

OAR Mean Dose (Gy) Mean Dose with Mantle Field (Gy)

Lungs 5.1 15–20 Gy

Heart 3.0 20–25 Gy

LAD 6.5

LV 0.6

L breast 0.5 15–20 Gy

R breast 0.1 15–20 Gy

lung metrics is especially important in salvage RT for mediastinal HL, disease [<7.5 cm]) DLBCL to 6 versus 4 cycles of R-CHOP, showed
and as much as possible, volume of lungs receiving 5 Gy (lung V5) that 4 cycles of chemotherapy plus two doses of rituximab are non-
should be kept below 55%. inferior to 6 cycles. Indications for adjuvant RT are controversial and
have evolved over time. Table 95.4 summarizes studies that explored
Non-Hodgkin Lymphoma the role of RT after R-CHOP chemotherapy, prior to the routine
use of PET, to assess response to chemotherapy. Findings from these
Non-Hodgkin lymphoma is a heterogeneous disease. The two most studies suggest a role for adjuvant RT in patients with initial skeletal
common histologic subtypes are diffuse, large B-cell lymphoma involvement or bulky disease (≥7.5 cm). However, it is notable that
(DLBCL) and follicular lymphoma (FL). The role of RT in DLBCL two of the studies were retrospective subgroup analyses of prospective
is evolving, especially in the era of PET-guided therapy. In FL, RT trials and thus prone to selection biases. Importantly, there were no
alone may play a curative role in patients with limited-stage disease. PET assessment at the end of chemotherapy.
Marginal zone lymphoma or mucosa-associated lymphoid tumor More recently, a number of studies have become available, address-
(MALT) is highly responsive to RT; similar to FL, RT alone can be ing the role of RT in the setting of complete PET response to chemo-
curative in patients with limited-stage disease. therapy. The LYSA/GOELAMS 02–03 trial randomized patients with
non-bulky (<7 cm), limited-stage DLBCL to 4 to 6 cycles of R-CHOP,
Diffuse Large B Cell Lymphoma delivered once every 2 weeks with or without RT, to a dose of 40 Gy if
a complete PET response was achieved after 4 cycles and at the end of
Current standard of care for DLBCL is systemic treatment with chemotherapy. At a median follow-up of 64 months, 5-year EFS (89%
rituximab, cyclophosphamide, doxorubicin, vincristine, and pred- vs. 92%) and OS (92% vs. 96%) was not statistically significantly dif-
nisone (R-CHOP) and has typically consisted of 6 cycles of che- ferent between the R-CHOP arm versus R-CHOP + RT.12 S1001, a
motherapy. However, in patients with limited-stage disease, results phase II study of non-bulky (<10 cm), limited-stage DLBCL, treated
of the FLYER trial, randomizing patients aged 18 to 60 years with patients with 3 cycles of R-CHOP, followed by interim PET-CT, with
limited stage, low-risk (normal serum lactate dehydrogenase con- PET-negative patients proceeding with 1 additional cycle of R-CHOP
centration, ECOG performance status 0 to 1, and without bulky and PET-positive patients receiving IFRT, followed by ibritumomab

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 1588 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

TABLE
95.2 Trials on Radiation Dose Reduction in Early-Stage Hodgkin Lymphoma

GHSG HD105,6 GHSG HD115,7

Number of Patients 1370 1395

Patient Characteristics Low risk: 1–2 sites, non-bulky, no E-lesions, ESR High risk: ≥ 3 sites, bulky med, E-lesions or ESR
<50 or <30 with B symptoms >50 or >30 with B symptoms
Treatment Arms ABVD x 4+30 Gy IFRT BEACOPP x 4+30 Gy IFRT
ABVD x 4+20 Gy IFRT BEACOPP x 4+20 Gy IFRT
ABVD x 2+30 Gy IFRT ABVD x 4+30 Gy IFRT
ABVD x 2+20 Gy IFRT ABVD x 4+20 Gy IFRT
Median Follow-Up 90 months 82 months
8-year Freedom from Tumor Failure (FFTF) 87% 87%
90% 87%
86% 85%
86% 81%
8-year Overall Survival (OS) 95% 95%
95% 95%
94% 94%
95% 94%
10-year Progression Free Survival (PFS) ABVD × 4 + 30 Gy IFRT [87.4%] ABVD × 4 + 30 Gy IFRT [83.9%]
ABVD × 2 + 20 Gy IFRT [87.2%] ABVD × 4 + 20 Gy IFRT [75.6%]

ABVD, Adriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone;
GHSG, German Hodgkin Study Group; IFRT, involved field radiation therapy; PFS, progression-free survival.

TABLE Trials on Omission of Radiation Therapy in Patients With Complete Positron Emission Tomography Response to Chemotherapy
95.3 in Early-Stage Hodgkin Lymphoma
RAPID EORTC/GELA/FIL GHSG HD1610 GHSG HD1711

H10F H10U
Number of Patients 420 551 594 628 1100
Patient Characteristics Stage I-IIA, non- Favorable per EORTC Unfavorable per Favorable per Unfavorable per GHSG
bulky EORTC GHSG
PET Negative Definition Deauville 1–2 ≤ Mediastinal blood Deauville 1–2 Deauville 1–2
pool level
Chemo Alone ABVD × 3 ABVD × 4 ABVD × 6 ABVD × 2 eBEACOPP × 2, ABVD
×2
5 y PFSPer - Protocol 88.6% 87% 89.6% 86.1% 95.1%
90.8%
Combined Modality Therapy ABVD × 3 + RT ABVD × 3 + RT ABVD × 4 + RT ABVD × 2 + RT eBEACOPP × 2, ABVD ×
2 + RT
5 y PFSPer-Protocol 92.3% 99% 92.1% 93.4% 97.3%
97.1%

ABVD, Adriamycin, bleomycin, vinblastine and dacarbazine; eBEACOP, dose-escalated: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
and prednisone; EORTC, European Organization for Research and Treatment of Cancer; GHSG, German Hodgkin Study Group; PET, positron emission tomography; PFS,
progression-free survival; RT, radiation therapy.

tiuxetan radioimmunotherapy. With a median follow-up of 4.5 years, time to progression was 83% among PET-negative patients who were
the 5-year PFS was 87% and OS was 89%, with only 11% of patients treated with chemotherapy alone. The excellent results suggest that RT
having a positive PET and requiring RT. The authors concluded that may not be needed if a complete metabolic response is achieved. In
R-CHOP × 4 alone, in patients with complete PET response, should patients with PET-positive disease at the end of chemotherapy, treated
be standard of care for limited-stage, non-bulky DLBCL in the major- with or without RT, the 3-year time to progression rates were 69% and
ity of patients.13 A retrospective series from British Columbia Cancer 33%, respectively, reflecting the important role of RT in those who lack
Agency reported on the outcome PET-guided RT in 723 patients with complete metabolic response. Among 285 patients with bulky disease
advanced stage DLBCL, treated with at least 6 cycles of R-CHOP, (≥10 cm) and among 142 patients with skeletal involvement, the 3-year
with observation of those with a negative PET-CT at the end of che- time to progression rates were similar to those of non-bulky patients,
motherapy. In patients with PET positive scans, consolidative RT was despite omission of RT. A longer follow-up may be needed to confirm
offered, when feasible. At a median follow-up of 4.3 years, the 3-year the efficacy of chemotherapy alone in these subgroup of patients who

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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1589

TABLE Studies in Diffuse Large B-Cell Lymphoma that Explored the Role of Radiation Therapy After R-CHOP (Rituximab,
95.4 Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) Chemotherapy Prior to the Routine Use of Positron Emission
Tomography Imaging to Assess Response to Chemotherapy
Study RT Decision Results

Retrospective subgroup analysis of patients with RT to skeletal sites per treating physician 3-year EFS
skeletal involvement from MInT and RICOVER-60 discretion RT: 75%
trials
No RT: 36%, P < .001
Retrospective subgroup analysis of patients with Before amendment: EFS
bulky disease (≥7.5 cm) from RICOVER-60 trial RT for bulky disease RT: 80%
After amendment: No RT: 54%, P = .001
No RT PFS
RT: 88%
No RT: 62%, P < .001
OS
RT: 90%
No RT: 65%, P = .001
UNFOLDER For patients with bulky disease ≥7.5 cm, Second planned interim analysis:
RT assessed in a randomized fashion after 3-year EFS
R-CHOP-14/21
RT: 84%
No RT: 68%, P = .001
No difference in 3-year PFS, OS

EFS, Event-free survival; OS, overall survival; PFS, progression-free survival; RT, radiation therapy.

may be at higher risk for local recurrence. Based on these recent results, symptomatic sites, is associated with minimal toxicity, and can poten-
the role of RT in patients with DLBCL is largely limited to patients tially delay the need to start systemic therapy. Multiple retrospective series
who lack complete PET response to R-CHOP or R-CHOP-like che- demonstrated overall response rates of 80% to 90%. Results from the
motherapy, although cases with initial bulky disease or dominant skel- FoRT trial, comparing 4 Gy in 2 fractions versus the 24 Gy in 12 frac-
etal sites of involvement, as well as receipt of suboptimal chemotherapy tions, showed a statistically significant difference in overall response rate
due to age, comorbidities, or other circumstances might still necessitate between the lower and higher doses (71.4% vs. 81%; P = .006), as well
or benefit from RT as part of treatment. as worse PFS (80.4% vs. 93.7%; P < .001), indicating that the low-dose
In terms of treatment dose, a trial by Lowry et al. showed that approach is generally not appropriate for patients with limited-stage dis-
at a median follow-up of 5.6 years, there was no difference in free- ease as curative intent (see the box with Case 2).18
dom from local progression and OS in patients treated with 30 Gy Marginal zone B-cell lymphoma (MZL or MALT) comprises 10%
in 15 fractions, compared to 40 to 45 Gy in 20 to 23 fractions.14 A of NHL. The majority of cases are localized at presentation and tend
phase II trial from Duke, using 20 Gy in patients with complete PET to remain localized for long periods of time. This subtype of lym-
response to chemotherapy, showed that with a median follow-up of phoma is highly responsive to RT. Doses of around 30 Gy to involved
51 months, the 5-year freedom from local recurrence was 98%, and nodal regions or extranodal sites will yield a local control rate of close
the 5-year PFS and OS were 83% and 90%, respectively.15 This lower to 100%, with a chance of long-term cure in about three-quarters
dose is currently being studied in a multi-center phase II trial. of the patients. Results from the previously described randomized
trial by Lowry et al. in which MALT lymphomas comprise 14% of
the cases, suggested that 24 Gy is adequate. Relapses tend to occur at
Indolent Lymphoma other extranodal sites in which MALT lymphomas tend to present
or in a non-irradiated contralateral paired organ. The likelihood of
For patients with limited stage FL, RT alone has been shown in ret- achieving a second remission in patients with limited relapses remains
rospective studies to result in a 10-year DFS of 40% to 50%. An excellent with further local RT.
international multicenter study, conducted by ILROG that included
only PET-staged patients, found a 5-year freedom from progression
(FFP) of 68.9%. Additionally, among patients with stage I disease, Relapsed/Refractory Diffuse Large B-Cell Lymphoma
the 5-year FFP was 74.1%, suggesting potentially better results of
RT in patients who have been more accurately staged.16 In terms of In patients with relapsed/refractory DLBCL, results of the landmark
optimal dose, the prospective, randomized trial by Lowry et al. found PARMA trial, published in 1995, established high-dose therapy and
no differences in local progression, PFS, or OS, with 24 Gy in 12 autologous transplantation as the standard for patients with chemo-
fractions compared to the traditional 40 to 45 Gy in 20 to 30 frac- therapy-sensitive disease. The indications of and general approaches
tions in patients with indolent lymphoma. This resulted in the adop- to peri-transplant RT are similar to that for relapsed/refractory HL
tion of 24 Gy as the standard radiation dose for early-stage, indolent and have been detailed in guidelines put forth by ILROG. One key
lymphomas. TROG 99.03 compared IFRT alone versus IFRT and difference is that for chemotherapy-refractory DLBCL, a higher dose
cyclophosphamide, vincristine, and prednisone (CVP), with ritux- of up to 50 Gy in conventional fractionation, or hyperfractionated
imab added later in the trial. The addition of systemic therapy to approach of 1.3 to 1.5 Gy/fraction twice daily to 35 to 40 Gy, may
IFRT showed a PFS benefit but no improvement in OS.17 be needed.
The majority of patients with FL present with advanced-stage disease. The advent of chimeric antigen receptor T-cell (CAR-T) therapy
In these patients, and in patients with recurrent disease, low-dose RT of has changed the landscape in management of relapsed/refractory
4 Gy in 2 fractions provides effective palliation in those with localized DLBCL. There is an emerging role for RT as bridging therapy as

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 1590 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

CASE 2
A 70-year-old man with stage IV follicular lymphoma, grade 1 and The patient noted resolution of proptosis and diplopia approximately 2
2, presented with slowly progressive proptosis and diplopia. Imaging weeks after the 2 doses of RT. He did not experience any side effects
revealed a left lateral rectus mass. Biopsy was consistent with underly- other than slight fatigue. Follow-up CT scan at 1-year post-treatment
ing follicular lymphoma: showed continued local disease control:

Low-dose palliative radiation therapy, 4 Gy in 2 fractions was recom-

mended. Aquaplast mask was used for immobilization, and the clinical
target volume (CTV) included the entire orbital content. 3D conformal
radiation therapy (RT) was used:

consolidation after CAR-T therapy or as salvage for further relapses Multiple Myeloma and Plasmacytoma
after CAR-T therapy. Several small, single institution series, have
recently been published, highlighting these approaches. These stud- For patients with multiple myeloma, RT plays an important role in the
ies provide early results showing that incorporation of RT to CAR-T palliation of painful bone lesions or less commonly soft-tissue disease,
therapy is generally safe and provides excellent local response and lytic lesions at risk for pathologic fractures in weight-bearing regions,
symptom control, prior to the infusion of CAR-T-cell product. RT and symptoms of cord or nerve root compressions for patients. A
may also lead to less severe cytokine release syndrome and neuro- dose of 20 Gy in 5 fractions can provide effective palliation, although
toxicity by providing disease debulking. The optimal timing, dose, in cases of cord compression, a higher dose of 30 Gy in 10 fractions
fractionation schedule, long-term toxicity, and efficacy remain to be may be needed. Solitary plasmacytoma accounts for 5% to 10% of all
determined. plasma-cell dyscrasias. For solitary plasmacytoma, RT to doses of 40

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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1591

to 50 Gy can provide effective local control of over 80%. In cases of to HD-MTX was explored in a phase II study from Memorial Sloan
solitary plasmacytoma of the bone, about half of the patients will prog- Kettering Cancer Center (MSKCC), showing high response rates, long-
ress to multiple myeloma at 10 years; by 15 years, most will develop term disease control, and minimal neurotoxicity. Results of the NRG-
multiple myeloma. Extraosseous solitary plasmacytoma is associated RTOG 1114 randomizing patients to low-dose WBRT of 23.4 Gy versus
with a lower risk of progression to multiple myeloma and has a more non-RT after chemotherapy were recently presented in abstract form. At
favorable disease-free survival. Guidelines from ILROG provide rec- a median follow-up of 55 months, the median PFS was 25 months in
ommendations on optimal RT management in these patients. the chemotherapy alone arm, and it was not reached in the chemother-
apy and WBRT arm (P = .015). The 2-year PFS were 54% and 78%,
Leukemia respectively. Neurotoxicity rates were not significantly different between
the two arms. However, additional neuropsychological testing and neu-
Myeloid sarcoma, also known as chloroma, is a rare tumor most roimaging analyses are still ongoing to fully characterize cognitive decline
commonly seen in the setting of acute lymphoblastic leukemia associated with the WBRT treatment.21
(ALL) and acute myelogenous leukemia (AML). ILROG guidelines Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is
are available on the use of radiation in the setting of CNS relapses, commonly seen in East Asia but rare in North America and Europe.
isolated chloroma with inadequate response to chemotherapy, or Approximately, 80% of cases involve the nasal cavity and present as
after hematopoietic stem cell transplant. RT is also used as pallia- erosive and destructive lesions. In patients with localized disease, the
tion, including in emergent symptomatic situations, such as cord or treatment approach is non-anthracycline-based chemotherapy regi-
nerve root compression. A dose 24 Gy in 2 Gy per fraction can be mens, including etoposide and L-asparaginase, in combination with
used in most cases, resulting in excellent and rapid responses, with RT. A commonly used regimen in the United States is RT concur-
overall durable control and symptom relief. Doses as low as 6 Gy can rently with 2/3 dexamethasone, etoposide, ifosfamide, and carboplatin
provide effective palliation in patients with limited life expectancy. (2/3DeVIC). To facilitate radiation target volume delineation, in addi-
Total body irradiation (TBI) is used as part of the conditioning regi- tion to PET-CT, MRI is important for an accurate determination of
men for myeloablative or non-myeloablative hematopoietic stem cell soft-tissue disease extent in radiation planning. Radiation dose of 50 to
transplantation in selected patients with ALL, AML, and other hemato- 54 Gy in conventional fractionation is recommended. In the setting of
poietic conditions. Technique is variable and based on treatment center. locally-advanced or stage IV disease, the dexamethasone, methotrex-
ILROG guidelines list the most common TBI schedules, delivering 12 to ate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen, with
13.5 Gy total over 3 to 4.5 days in 1.2 to 3.0 Gy per fraction. To reduce sequential RT as indicated, can provide effective disease control.22
short- and long-term effects of TBI, interest has been increasing in total Primary mediastinal B-cell lymphoma (PMBL) is a distinct clini-
marrow and lymphoid irradiation (TMLI), using tomotherapy or volu- copathological entity of lymphoid malignancies, originating from
metric modulated arc therapy (VMAT) techniques to limit target doses B-cells of the thymus. A phase II trial from the National Cancer
to bone marrow, lymphoid tissue, and sanctuary sites. Institute found excellent outcome, using 6 cycles of dose-adjusted
etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin,
Skin Lymphoma and rituximab (EPOCH-R) but without RT. At a 5-year median
follow-up, the EFS and OS rates were 93% and 97%, respectively. In
Primary cutaneous lymphoma is highly radiation sensitive, with RT a recent abstract reporting on the subgroup of 131 PMBL from the
playing a major role in its management. The most common type of previously described UNFOLDER trial, patients assigned to the RT
cutaneous T-cell lymphomas (CTCL) is mycosis fungoides (MF). Total arm after R-CHOP chemotherapy had a superior 4-year EFS (94%
skin electron beam therapy (TSEBT) can provide effective palliation vs. 78%; P = .007), mostly due to a higher partial response rate
for this disease, and doses of 8 to 36 Gy have been used, with higher in the non-RT arm, triggering RT but no difference in PFS (95%
doses allowing more durable control. However, a lower TSEBT dose of vs. 90%) or OS (98% vs. 96%).23 The role of mediastinal RT, after
10 to 12 Gy is increasingly accepted because of the shorter treatment a complete PET response to rituximab-containing chemotherapy
course, fewer side effects, and opportunity for repeated treatment if regimens in patients with PMBL, is currently being addressed by the
needed. The most commonly encountered cutaneous B-cell lymphoma International Extranodal Lymphoma Study Group (IELSG) 37 trial.
(CBCL), seen in a radiation oncology practice, are primary cutaneous Primary testicular lymphoma, usually pathologically diagnosed as
follicle center lymphoma and cutaneous marginal zone lymphoma. In an extranodal DLBCL of the testis, affects primarily men over the age of
patients with solitary or localized disease, a dose of 24 to 30 Gy can 50. There is a high propensity for CNS relapses, and as such CNS pro-
be potentially curative. Otherwise, low doses of 4 Gy in 2 fractions or phylaxis with either intrathecal or intravenous methotrexate is included
8 Gy in 1 to 2 fractions in CBCL and CTCL, respectively, can provide as part of upfront treatment. In addition, there is an increased risk of
effective local palliation, with complete response rates of 70% to 90%. contralateral testicular relapse, occurring in 15% of patients at 3 years,
Details on technique, field, and dose guidelines for the various histolo- with an increase to 42% at 15 years. Prophylactic scrotal irradiation of
gies and clinical scenarios have been published by ILROG. 25 to 30 Gy in 10 to 15 fractions can significantly reduce the risk. A
phase II study by the IELSG showed that with the addition of intrathe-
Rare/Miscellaneous and Special Situations cal methotrexate to R-CHOP chemotherapy and 30 Gy of RT to the
contralateral testis the cumulative risk of CNS relapse was reduced to
Primary central nervous system lymphoma (PCNSL) most commonly 6%. No contralateral relapse was seen in the 53 treated patients.24
presents in the brain parenchyma, followed by leptomeninges, spinal
cord, and ocular via vitreous and retinal seeding. High-dose methotrex-
ate (HD-MTX)-based induction chemotherapy is considered standard DOSE CONSTRAINTS AND TOLERANCES
for newly diagnosed PCNSL. The role of RT as part of upfront treat-
ment has been evaluated by several randomized trials. Thiel et al. con- When considering dose constraints and tolerances in the setting of
ducted the first phase III trial, comparing whole brain radiation therapy hematologic malignancies, it is important to keep in mind the young
(WBRT) to a dose of 45 Gy versus non-RT, after HD-MTX-based age of a significant proportion of patients, often with highly curable
therapy in PCNSL, showing improved PFS (HR = 0.79, P = .041) in disease and a long-life expectancy. Minimization of doses to sur-
the WBRT group but at the expense of higher neurotoxicity; no OS dif- rounding organs-at-risk is therefore especially important, aiming for
ferences occurred between the two arms.19 More recently, a randomized the lowest possible dose to normal structures, while maintaining ade-
phase II trial on patients with PCNSL, aged 18 to 60 years, compared quate target coverage using modern radiation technology. Moreover,
WBRT (40 Gy) versus autologous stem-cell transplantation (ASCT) as because of the modest doses of radiation typically used in the treat-
consolidation treatment after induction chemotherapy. The 2-year PFS ment of hematologic malignancies, dose constraints used in solid
rates were 63% and 87% in the WBRT and ASCT arms, respectively, tumors do not apply to most lymphoma patients. Another important
with increased cognitive impairment seen on the WBRT arm.20 The use consideration is that many hematologic malignancy patients present-
of a lower WBRT dose of 23.4 Gy in patients with complete response ing for RT may have previously been exposed to one or more lines of

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 1592 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

systemic therapies, with toxicities to specific organs, including heart,

TABLE Dose Constraints for Organs at Risk Based on Proton
lungs, gastrointestinal track, CNS, and bone marrow. Depending on
95.5 Therapy Use in Mediastinal Lymphoma
the site of irradiation, special attention to organs that are at risk for
overlapping toxicity needs to be made. Table 95.5 summarizes dose Dose Constraint
constraints recommended by ILROG for mediastinal lymphoma RT.
Avoid Max
Organ Ideal Unacceptable Dose To

SUMMARY OF GUIDELINES Heart: left Mean <5 Gy Mean >30 Gy Coronary

ventricle, vessels
Tables 95.6 and 95.7 list the current recommended dose and fraction- coronary
ation for curative and palliative RT, respectively, based on ILROG arteries, valvesa
published guidelines. References to the ILROG published guidelines Lunga Mean <10 Gy Mean >13.5 Gy —
are listed under suggested readings.
V5 <55% V5 >60%
FUTURE DIRECTIONS V20 <30%
Breast (age Mean <4 Gy Mean >30 Gy Glandular
As advances in technology continue to improve the prognosis of lym- dependent) a tissue
phoma, special attention will be necessary to optimize outcomes, while
Thyroida V25 <62.5% — Whole
reducing unnecessary harms. The importance of patient selection and
thyroid
evaluation of individualized de-escalation or intensification approaches
based on treatment response, will require a team-based approach. aDoses obtained from Guide to acceptable dose, volume, and field considerations
Emphasis on individualized treatment recommendations will continue (Table 2) in Dabaja BS, Hoppe BS, Plastaras JP, et al. Proton therapy for adults
to require the integration of multidisciplinary teams, with consideration with mediastinal lymphomas: the International Lymphoma Radiation Oncology
of individual patients’ presentation, clinical picture, and goals of care. Group guidelines. Blood. 2018;132(16):1635–1646.

TABLE Summary of the International Lymphoma Radiation Oncology Group Guideline Recommendations for Hematologic
95.6 Malignancy Cases Treated with Curative Intent
Histology and Stage Systemic Tx Total Dose (Gy) Number of Fractions

Hodgkin Lymphoma—Limited Stage, Favorable ABVD × 2 20 10

Hodgkin Lymphoma—Limited Stage, Unfavorable ABVD × 3–4 30 15
Relapsed/Refractory Hodgkin Lymphoma Salvage chemotherapy, ASCT Peri-transplant RT: 20
If CR, 30–36
Boost to PR site(s):
36–40
Nodular Lymphocyte Predominant Hodgkin Lymphoma—Limited None 30 15
Stage
Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP × 3–6 If CR, 30 15
If PR, boost to 20–25
40–45
Indolent Lymphoma—Limited Stage None 24 12
Natural Killer (NK)/T-cell Lymphoma Non-anthracycline-based Concurrent or 25–30
chemotherapy, e.g., DeVIC sequential with
SMILE chemotherapy:
45–54
Cutaneous Lymphoma, Solitary None 24–30 12–15
Solitary Plasmacytoma None 40–50 20–25

ABVD, Adriamycin, bleomycin, vinblastine and dacarbazine; ASCT, autologous stem cell transplantation; DeVIC, dexamethasone, etoposide, ifosfamide and carboplatin;
RT, radiation therapy; SMILE, dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide.

TABLE Summary of the International Lymphoma Radiation Oncology Group Guideline Recommendations for Hematologic Malignancy
95.7 Cases Treated with Palliative Intent Radiation Therapy
Histology Total Dose (Gy) Number of Fractions

Aggressive Non-Hodgkin Lymphoma (NHL) 8–30 (depending on performance status, life expectancy, treatment site, prior 1–10
radiation therapy history)
Multiple Myeloma 20 30 (if cord compression) 5
10
Follicular Lymphoma, Marginal Zone Lymphoma 4 2
Myeloid Sarcoma/Leukemia 24 12
Limited life expectancy: 3
6

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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1593

SUGGESTED READINGS International Lymphoma Radiation Oncology Group. Int J Radiat Oncol
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with relapsed or refractory Hodgkin lymphoma: guidelines from the 2015;92(1):32–39.
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 Chapter 95 Principles of Radiation Therapy for Hematologic Disease 1593.e1

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