REVIEW ARTICLE
Improvements in Imaging of Hodgkin Lymphoma
Positron Emission Tomography
Martin Hutchings, MD, PhD
Abstract: 18-Fluoro-2-deoxy-D-glucose positron emission tomography/
computed tomography (FDG PET/CT) is currently the criterion standard of
lymphoma imaging and recommended through all stages of Hodgkin lym-
phoma management. Accurate staging is important for risk stratification and
initial choice of therapy and also for the planning of postchemoradiotherapy.
18-Fluoro-2-deoxy-D-glucose PET/CT frequently leads to upstaging and
potentially a more intensive treatment. Visual-only assessment of staging
Downloaded from http://journals.lww.com/journalppo by BhDMf5ePHKbH4TTImqenVE+K0QyTIVibDcw+ETK+CicVhvIEvCroWgbMpGz+ry+n on 10/08/2018
and interim scans is being accompanied by quantitative and semiquantita-
tive methods to measure metabolic tumor volume, total lesion glycolysis,
and so on. It is still unclear if these methods significantly improve the value
of FDG PET/CT by visual assessment only. Because of the good prognos-
tic value of FDG PET/CT, a large number of studies have used interim
FDG PET to tailor treatment to the individual patients, according to their
early metabolic response rather than according to their pretreatment prog-
nostic features. 18-Fluoro-2-deoxy-D-glucose PET/CT is standard of care
for posttreatment response assessment but has no place in routine follow-
up of Hodgkin lymphoma patients in remission.
Key Words: Hodgkin, lymphoma, PET, positron emission tomography
(Cancer J 2018;24: 215–222)
P ositron emission tomography (PET) with the 18-fluoro-2-deoxy-
D-glucose (FDG) tracer was introduced some 20 years ago. A
few years later, PET was incorporated with computed tomography
(CT) into combined PET/CT scanners, and since then, FDG PET/
CT has become the most important imaging technique in the man-
agement of Hodgkin lymphoma (HL).1
Whereas normal cells primarily produce energy through mi-
tochondrial oxidative phosphorylation, cancer cells predominantly
produce their energy through a high rate of glycolysis followed by
lactic acid fermentation even in the presence of oxygen.2 Aerobic
glycolysis is less efficient than mitochondrial oxidative phosphor-
ylation, explaining why cancer cells have an increased need for
glucose. This leads to an up-regulation of glucose transporting
membrane proteins in the cell (GLUT-1 to GLUT-5).3 Cancer cells
furthermore have a high activity of hexokinase. The glucose ana-
log FDG is transported to the cell by GLUT transporters, particu-
larly GLUT-1. In the cell, FDG is phosphorylated by hexokinase
to FDG-6-phosphate, which does not cross the cell membrane.
Because of the low levels of glucose-6-phosphatase in cancer cells
and the inability of FDG-6-phosphate to further enter glycolysis, the
tracer is trapped in the cancer cells.4 18-Fluoro-2-deoxy-D-glucose
is not a specific marker for malignancy because it is also accumu-
lated in the nonmalignant tissues with increased glucose metabo-
lism. This probably explains why HL has a very high FDG avidity,
From the Department of Haematology, The Finsen Centre, Rigshospitalet, Co-
penhagen, Denmark.
The author has disclosed that he has no significant relationships with, or
financial interest in, any commercial companies pertaining to this article.
Reprints: Martin Hutchings, MD, PhD, Department of Haematology, The
Finsen Centre, Rigshospitalet, Copenhagen, Denmark. E‐mail:
martin.hutchings@regionh.dk.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1528-9117
The Cancer Journal • Volume 24, Number 5, September/October 2018
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
even though the malignant cells make up only approximately 1%
of all tumor cells and are surrounded by noncancerous mono-
nuclear cells, the metabolism of which are regulated by the clonal
Hodgkin/Reed-Sternberg cells.
In the absence of good and easily measureable disease markers
in blood, imaging plays a critical role in the management of patients
with lymphomas. Historically, in HL, planar x-ray images were
combined with bone marrow biopsy, lymphoscintigraphy, and di-
agnostic laparotomy.5 The introduction of CT enabled noninvasive
visualization of the inner organs and made lymphoscintigraphy and
diagnostic laparotomy obsolete.6 With the introduction of FDG
PET and FDG PET/CT, HL staging and response assessment are
no longer based only on anatomical imaging, but also on dynamic
assessment of tumor physiology. Modern, state-of-the-art FDG
PET/CT provides images of FDG metabolism with anatomical
correlations provided by CTand this way gives a very clear picture
of the anatomical and functional characteristics of lymphomas be-
fore, during, and after treatment.1 As the most accurate imaging
tool in HL, FDG PET/CT plays a crucial role the management
of this disease both before and during treatment.
PET/CT FOR HL STAGING
The first reports on FDG PET for lymphoma imaging were
published more than 30 years ago.7 Studies of HL patients showed
not only a very high sensitivity of FDG PET for nodal staging, espe-
cially for the detection of peripheral and thoracic lymph nodes, but
also high rates of false-positive findings. 18-Fluoro-2-deoxy-D-glu-
cose PET detected more disease sites, nodal as well as extranodal,
than conventional imaging methods, resulting in a higher sensi-
tivity and leading to significant upward stage migration.8–10 How-
ever, when performed as PET/CT, the increased sensitivity does
not come at the expense of a decreased specificity.11 PET/CT also
detects extranodal disease more sensitively than conventional
methods, both in the bone marrow and in other organs, and seems
to be at least as sensitive as blind BMB.11,12 A study of 454 HL
patients with staging BMB and PET/CT showed no value of rou-
tine BMB in the era of PET/CT staging, and as a consequence,
BMB has been abandoned as a routine staging investigation in
HL.1,13 An example of FDG PET/CT staging with detection of
bone marrow involvement is seen in Figure 1.
Several studies have shown that PET/CT has a consistent,
large influence on the staging in classic HL, with upstaging of ap-
proximately 15% to 25% of patients and downstaging in only a
small minority of patients. This leads to a shift to a more advanced
treatment group in approximately 10% to 15% of patients.11,14,15
In a comparison of FDG PET/CT and CT in the 1171 HL patients
included in the Response-Adapted Therapy in Hodgkin Lym-
phoma (RATHL) study of early PET response–adapted therapy
in advanced-stage HL, FDG PET/CT resulted in upstaging in
14% of the patients, primarily as a result of bone marrow involve-
ment not detected by bone marrow biopsy or normal-sized lymph
nodes with FDG uptake. Downstaging by FDG PET/CT occurred
in 6% of the patients and was most often a result of splenomegaly
or enlarged lymph nodes with normal FDG uptake.16 A single
www.journalppo.com 215
Hutchings The Cancer Journal • Volume 24, Number 5, September/October 2018
FIGURE 1. Maximum intensity projection image from a
pretreatment FDG PET scan of a patient with newly diagnosed
stage IV Hodgkin lymphoma. Pathological FDG uptake is seen in
multiple lymph nodes above and below the diaphragm as well as
in the spleen and bone marrow.
study has shown a similar pattern in nodular lymphocyte predom-
inant HL, where staging FDG PET resulted in changes of stage
in 9 of 31 patients (7 upstagings and 2 downstagings).17 The ten-
dency toward upward stage migration is important because early
and advanced disease stages of HL are treated very differently. How-
ever, early-stage HL patients (regardless of the staging methods)
have an excellent prognosis and are at risk of serious treatment-
related late morbidity and mortality. With this in mind, the use
of FDG PET/CT for staging of HL should be accompanied by steps
to reduce the overall intensity of therapy, and this, fortunately to
some extent, has been achieved, as described in the following.
The advances of modern radiotherapy for HL have led to dra-
matic reductions in the volume of normal tissue being irradiated
and expected similar reductions in the risk of serious late effects
of radiotherapy, as covered elsewhere in this issue.18,19 Such highly
conformal therapy is only feasible with access to the most accu-
rate imaging procedures used for treatment planning. Because
PET/CT is more accurate for staging of HL, it is by implication
also more precise in defining the initially involved regions or
nodes that are intended to be irradiated in patients with early-stage
disease. In the setting of modern conformal radiotherapy tech-
niques such as involved-site radiotherapy and involved-node
radiotherapy, the definition of the involved nodes and thus the
radiotherapy volumes are significantly different with PET/CT
versus CT alone, both in classic HL and nodular lymphocyte
predominant HL.17,20,21
216 www.journalppo.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Thus, in summary, FDG PET/CT is the current mainstay of
HL staging and recommended as such by current international
HL guidelines.1,22–24 Positron emission tomography/CT provides
the best available staging accuracy and thus the best possible basis
for treatment selection and for modern, conformal radiotherapy
planning. The upward stage migration caused by PET/CT carries
a risk of further overtreatment but is counterweighed by signifi-
cant reductions in the radiotherapy volumes and particularly by
the introduction of early PET response–adapted treatment with
the purpose of reducing the overall treatment burden. The commu-
nity should keep aware that the significant upward stage migra-
tion will bias comparisons of current treatment strategies with
historical data.25
Ann Arbor staging is a rather crude measure of disease bur-
den and dissemination. A number of studies have in recent years
analyzed the value of quantitative FDG PET/CT for risk stratifica-
tion in HL. In both de novo and relapsed HL, metabolic tumor
volume (MTV), which is a measure of the tumor volume with ab-
normal FDG uptake, is predictive of progression-free survival
(PFS).26,27 Another quantitative measure of baseline tumor bur-
den is total lesion glycolysis, which is the MTV multiplied by
the average standardized uptake value in the tumor sites. Total le-
sion glycolysis is predictive of PFS in HL but does not seem to
improve the risk stratification compared with MTV, indicating
that degree of FDG uptake in HL is of lesser importance than
the distribution.27,28
Early Interim PET in HL
Whereas clinical stage and prognostic factors are used to de-
termine the initial treatment strategy, the response to induction
treatment is strongly prognostic. A reliable and early prediction
of response to therapy could identify good-risk patients who will
be cured with conventional therapy or even less intensive and less
toxic regimens and poor-risk patients for whom an early switch to
alternative, more aggressive treatment strategies could improve
the chance of remission and cure. This concept called risk-adapted
therapy is widely recognized as one potential way to maintain and
even improve the high cure rates while minimizing the overall risk
of treatment-related morbidity and mortality.27–29
Before FDG PET, treatment response monitoring was based
on morphological criteria, and a reduction in tumor size on CT
was the most important determinant.30 However, size reduction
is not necessarily an accurate predictor of outcome. In HL, the
malignant cells make up only a small fraction of the tumor vol-
ume, which is dominated by reactive infiltrating cells probably
not directly affected by antineoplastic therapy,31 and even more
importantly, tumor shrinkage takes time and depends on a number
of factors in the host. So, often the rate of structural regression is
not suitable for therapy response assessment until rather late dur-
ing treatment, at which point a treatment modification might be
less useful.
Functional imaging with FDG PET enables early evaluation
of the metabolic changes that take place very early during the
treatment induction. Several studies of FDG PET and FDG PET/
CT after 1 to 3 cycles of chemotherapy32–38 have shown that these
early metabolic changes are highly predictive of final treatment
response and PFS.
A retrospective analysis of 88 patients scanned after 2 or
3 cycles of ABVD (adriamycin, bleomycin, vinblastine, and
dacarbazine)–like chemotherapy for HL showed a 5-year PFS of
39% in the PET-positive group compared with 92% in the PET-
negative group.32 These results were later confirmed in several
prospective studies,35–37 showing excellent outcomes for early
PET-negative patients (approximately 95% long-term PFS) and
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Cancer Journal • Volume 24, Number 5, September/October 2018
rather poor outcomes for early PET-positive patients. In patients
with advanced disease, the high prognostic value of early FDG
PET overshadows the role of the IPS.35,38 The prognostic value
of PET/CT in advanced HL was later validated by Gallamini
et al.,34 who showed 3-year failure-free survival of 28% and
95% for early PET-positive and early PET-negative patients, re-
spectively.34 In this international validation study, the interob-
server agreement was very high between 6 independent PET/CT
reviewers, using the Deauville criteria for interim PET, which have
become widely recognized.39,40 Apart from giving reproducible
results, the Deauville criteria are very simple in use; thus, their
use in most of the studies of PET response–adapted therapy en-
sures comparability between clinical trials and also enables a bet-
ter translation of clinical trial results into clinical practice outside
trials. Quantitative and semiquantitative methods for assessment
of FDG PET response have been applied in HL by several groups
to assist the visual assessment, and these methods may improve
the predictive values and reduce interobserver variation.41
The positive predictive value of early FDG PET seems to be
lower in patients treated with the more dose-intensive BEACOPPesc
(bleomycin, etoposide, doxorubicin, cyclophosphamide, vincris-
tine, procarbazine, prednisone) regimen than in patients treated
with ABVD.42 Also, the positive predictive value is lower in pa-
tients with early-stage HL, probably due to both the inherent better
prognosis for this patient group and due to the subsequent ra-
diotherapy, which may in many early-stage patients overcome an
insufficient chemotherapy response.43–45 Figure 2A shows an in-
sufficient response to chemotherapy after 2 cycles of ABVD.
PET Response–Adapted HL Therapy—Early- and
Advanced-Stage HL
More than 90% of early-stage HL patients are cured with
standard therapy. But the patients still have a significantly reduced
life expectancy due to treatment-related illness including second
cancers and cardiopulmonary disease. In fact, early-stage HL
patients more often die of late effects of therapy than from the dis-
ease itself.46 This suggests that a substantial number of early-stage
HL patients are subject to some amount of overtreatment, and it is
the background for using early PET/CT to identify good-risk
early-stage patients eligible for less intensive treatment. A number
of trials have investigated such PET response–adapted therapy
in early-stage HL. The UK National Cancer Research Institute
Lymphoma Group RAPID trial for early-stage patients as well
as the German Hodgkin Study Group HD16 protocol investigat-
ed the noninferiority of reducing treatment intensity by omitting
radiotherapy to interim PET-negative early-stage patients. The ex-
perimental arms of EORTC/GELA/FIL (European Organisation
for the Research and Treatment of Cancer/Groupe des Etudes
des Lymphomes de l'Adulte/Fondazione Italiana Linfomi) H10
protocol also omitted radiotherapy to interim PET-negative pa-
tients while escalating from standard ABVD chemotherapy to
more intensive (BEACOPPesc) chemotherapy followed by radio-
therapy in PET-positive patients. In other words, this trial tests the
noninferiority of a less toxic treatment (omitting radiotherapy) to
good-risk patients, while attempting treatment intensification for
patients regarded as having a high risk of failure based on a posi-
tive interim PET/CT. The results of the German HD16 trial have
not yet been published, but the RAPID trial and the H10 trial both
failed to demonstrate noninferior PFS in the chemotherapy-only
arms. In the UK RAPID study, patients who were PET negative
after 3 cycles of chemotherapy would be randomized to either
radiotherapy or no further treatment. At median 3 years of fol-
low-up, the PFS difference in the RAPID trial was 3.8 percentage
points (95% confidence interval [CI], 8.8–1.3) in favor of the
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Improvements in Imaging of Hodgkin Lymphoma
radiotherapy arm, thus failing to meet the predefined margin of
noninferiority, which was 7%. There was no difference in overall
survival (OS) between the 2 treatment arms.47 The European H10
trial stratified patients into favorable and unfavorable subgroups,
according to standard risk factors for early-stage HL.48 Patients
were randomized at baseline to standard therapy (combined mo-
dality, chemotherapy followed by radiotherapy) or an experimen-
tal FDG PET response–adapted treatment strategy. All patients
had an FDG PET after 2 cycles of chemotherapy (PET2). In the
experimental arms, PET2-negative patients were given chemo-
therapy alone, but the latter arms were stopped prematurely after
a futility interim analysis predicted failure of meeting the primary
endpoint, which was PFS noninferiority.49 The final analyses con-
firmed a loss of disease control when radiotherapy was omitted.48
PET2-positive patients in the experimental arm (including both
favorable and unfavorable risk groups) had their treatment in-
tensified with a shift to 2 cycles of more intensive chemotherapy
followed by radiotherapy. In the PET2-positive patients, PFS was
significantly superior when compared with the standard arm
where patients were treated with less intensive chemotherapy
followed by radiotherapy (5-year PFS, 90.6% vs 77.4%; hazard
ratio, 0.42 [95% CI, 0.23–0.74]).48 This difference was mainly
due to improved PFS of patients in the unfavorable risk group
who received intensified chemotherapy. Even without knowing
the results of the German HD16 study, we can conclude from
the RAPID and H10 studies that omitting radiotherapy in good-
risk (PET2-negative) patients results in a modest loss of disease
control (PFS), whereas there is no difference in OS.
Approximately 70% of advanced-stage HL patients are cured
with 6 cycles of ABVD chemotherapy with or without consolida-
tion radiotherapy, which is first-line therapy in most centers.
BEACOPPesc cures 85% to 90% of patients if given upfront,
but serious concerns regarding acute toxicity and second myeloid
neoplasias are the reason why many centers are reluctant to use
this regimen as standard therapy.50 Numerous trials have inves-
tigated PET response–adapted therapy for advanced-stage HL
patients. Three nonrandomized trials use early treatment intensi-
fication with BEACOPPesc (Italian GITIL0607 [Gruppo Italiano
Therapie Innovative nei Linfomi] trial and the UK RATHL trial)
or even high-dose chemotherapy with autologous stem cell sup-
port (Italian FIL trial) in patients who were still PET positive after
2 cycles of ABVD. The randomized German HD18 trial tested
abbreviation of BEACOPPesc therapy based on PET results
after 2 therapy cycles. The French AHL 2011 trial was also a
BEACOPPesc-based randomized trial with treatment modifica-
tions based of PET after both 2 and 4 cycles.
The UK RATHL study included 1214 patients with stage
IIB–IV or stage IIA with high-risk features who received 2 cycles
of ABVD followed by FDG PET. PET2-negative patients (Deau-
ville scores 1–3) were randomized to either continued ABVD (to-
tal of 6 cycles) or continued treatment without bleomycin (AVD).
The analyses of the PET2-negative patients showed no difference
in PFS between the 2 randomization arms (3-year PFS, 85.7% vs
84.4%).51 Even though in the primary analysis the results fell
just short of the specified noninferiority margin, an updated ana-
lysis showed that with extended follow-up the study had met its
primary endpoint of PFS noninferiority.52 PET2-positive patients
received more intensive chemotherapy with an additional 4 cycles
of BEACOPP14 or BEACOPPesc, resulting in a 3-year PFS
of 68%, comparing favorably with historical controls from ob-
servational studies in which ABVD was continued in PET2-posi-
tive patients.34,36,51 The Italian single-arm GITIL/FIL HD0607
(stage IIB–IV patients) study showed similar results from esca-
lation to eBEACOPP in patients PET positive after 2 cycles of
ABVD (3-year PFS, 57%). They also showed no improvement
www.journalppo.com 217
Hutchings The Cancer Journal • Volume 24, Number 5, September/October 2018

FIGURE 2. Same patient as in Figure 1. The “A” images show the interim PET/CT scan performed after 2 cycles of chemotherapy. Despite a
clear response, residual uptake is seen in the left hilar region (Deauville score 4). The “B” images show the same patient in disease
progression after completion of treatment, which was not adapted according to the early interim FDG PET.

of outcomes from consolidative radiotherapy to initially bulky
masses (>5 cm) in patients who were PET2 negative and remained
posttreatment PET negative.53 In the German HD18 study, all pa-
tients with advanced HL had 2 cycles of BEACOPPesc followed
by FDG PET. Patients in the standard arm would receive 8 cycles
of BEACOPPesc, but halfway during the study, the duration of
standard treatment was abbreviated to 6 cycles as a result of the
analysis of the German HD15 study. In the experimental arm,
PET2-negative patients (Deauville 1–2) would receive only an ad-
ditional 2 cycles of BEACOPPesc, so a total of 4 cycles. The final
analysis showed that in PET2-negative patients 4 cycles of therapy
were noninferior to 6 cycles in terms of 5-year PFS (90.8% vs
92.2%) and furthermore associated with significantly less acute
and late toxicity.54 PET2-positive patients continuing eBEACOPP
still had very high 3-year PFS of 87.6% (95% CI, 83.0%–92.3%),
illustrating that the positive predictive value of interim FDG PET
depends on the treatment setting. A subsequent analysis showed
no difference in outcome between patients in the standard arm
who had a Deauville score of 1 to 2 and those with a Deauville
score of 3 (the latter in many other studies would be considered
PET negative but in HD18 regarded as PET positive). This indi-
cates that abbreviation of BEACOPPesc therapy in early PET-neg-
ative patients should be done in patients with PET2 Deauville
scores of 3 as well as those with Deauville scores 1 to 2.55 The
French AHL2011 study aimed to assess whether interim FDG
PET could identify good-risk patients to be given de-escalation
treatment after upfront BEACOPPesc. A total of 823 patients
were randomized to the standard arm (n = 413) and the experi-
mental arm (n = 410). After a median follow-up of 50.4 months,
the 4-year PFS for the experimental arm was 87.1% and for the
standard arm was 87.4%, with no difference in OS, demonstrating
that treatment intensity can be safely reduced from BEACOPPesc
to ABVD in PET2-negative patients.56
Thus, in advanced-stage HL, early interim PET can be safe-
ly used to de-escalate therapy (reduction in number of cycles of
BEACOPPesc, reduction of intensity from BEACOPPesc to
ABVD, omission of bleomycin from ABVD) in PET2-negative
patients. At the same time, intensification to BEACOPPesc should
be considered with insufficient initial PET response to ABVD.
Postchemotherapy PET/CT for Selection of
Advanced-Stage HL Patients for
Consolidation Radiotherapy
In advanced HL, radiotherapy is used less frequently than in
early-stage HL and usually only to residual masses. Computed to-
mography cannot discriminate between a residual mass with viable
lymphoma cells and a residual mass consisting only of fibrotic tis-
sue. However, because PET/CT cannot detect microscopic dis-
ease, it was necessary to perform studies to investigate whether
a PET-negative residual mass requires radiotherapy. The mature
results of the German HD15 trial shed light on this for patients
treated with BEACOPP regimens. In the HD15 study, consolida-
tion radiotherapy was given only to patients with a PET-positive

218 www.journalppo.com © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

The Cancer Journal • Volume 24, Number 5, September/October 2018
residual mass of more than 2.5 cm. The remaining majority of pa-
tients who did not receive radiotherapy had a relapse-free survival
of 94% after 1 year, indicating that radiotherapy can be safely
omitted in advanced-stage HL patients who are PET negative after
the end of BEACOPPesc.57,58 A retrospective analysis from the
British Columbia Cancer Agency addressed the same situation
for patients treated with ABVD. The authors reported a 10-year
experience where patients with advanced-stage HL and residual
masses of larger than 2 cm after chemotherapy underwent PET/
CT (n = 163). Only patients with a positive posttreatment PET/
CT received radiotherapy. At the end of treatment, 316 patients
had residual masses larger than 2 cm and underwent PET/CT.
Of those, 264 (83.5%) were FDG PET negative, none of whom
received radiotherapy, and 52 (16.5%) were FDG PET positive,
of whom 79% (n = 41) received consolidative RT (30–35 Gy).
With a median follow-up for living patients of 4.6 years (range,
0.6–13.5 years), the 5-year freedom from treatment failure (FFTF)
for the whole cohort was 83%, and 5-year OS was 94.5%. Not
surprisingly, patients with a negative posttreatment FDG PET
had a superior 5-year FFTF compared with those with a positive
scan (89% vs 56%, respectively). In the posttreatment FDG
PET–negative group, there was no difference in outcome compar-
ing the bulky (n = 112) and nonbulky (n = 152) subgroups (5-year
FFTF 89% vs 88.5%, respectively). Similarly, when the analysis
was restricted to FDG PET–negative patients with a bulky medi-
astinal mass at diagnosis (n = 102), outcomes were excellent (5-
year FFTF, 89%; 5-year OS, 96%).59 These results support the
omission of radiotherapy to advanced-stage HL patients who re-
ceive a PET-negative remission after 6 cycles of chemotherapy.
PET/CT FOR FINAL RESPONSE EVALUATION
An extensive number of studies have shown that FDG PET
performed posttreatment is highly predictive of PFS and OS in
HL patients with and without residual masses on CT.60,61 Based
on these findings, the International Harmonization Project de-
veloped recommendations for response criteria for aggressive
malignant lymphomas, incorporating PET/CT into the definitions
of end-of-treatment response in FDG-avid lymphomas, including
HL, already in 2007.62 Subsequent retrospective analyses confirm
the superiority of these response criteria in HL compared with the
previous criteria, which were based on morphological imaging
alone.63 Posttreatment FDG PET/CT is still recommended in the
most recent guidelines for response assessment and the main de-
terminant for the distinction between complete (CR) and partial
response (PR).1,22 However, when addressing posttreatment
FDG PET/CT, it should be remembered that the positive predic-
tive value is lower than the negative predictive, particularly in
those patients treated with BEACOPPesc.57,64,65 This means that
a positive FDG PET/CT should not alone be regarded as evidence
of refractory disease. Figure 2B is an example of truly refractory
HL, showing progressive disease at the end of treatment, despite
a short and transient response early during chemotherapy.
PET/CT Before High-Dose Salvage Therapy in
Relapsed HL
For HL patients in first relapse, a number of risk factors pre-
dict outcome after high-dose chemotherapy with autologous stem
cell support (HD + ASCT).66 Two important factors are the dura-
tion of remission prior to relapse and the response to induction
therapy. A number of studies have shown that FDG PET per-
formed after induction therapy and before HD + ASCT can predict
which HL patients will achieve long-term remission after the sal-
vage regimen.67–69 These studies report a poor long-term PFS in
patients who are FDG PET positive after induction chemotherapy
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Improvements in Imaging of Hodgkin Lymphoma
(31%–41%), compared with a PFS of 73% to 82% in the patients
who reach a PET-negative remission before HD + ASCT. A study
from the Memorial Sloan Kettering Cancer Center investigated a
PET-guided approach where patients who were FDG PET positive
after the standard induction regimen ICE (ifosfamide, carboplatin,
etoposide) instead of proceeding to HD + ASCT were instead
given a non–cross-resistant regimen consisting of 4 biweekly
doses of GVD (gemcitabine, vinorelbine, and liposomal doxoru-
bicin) before HD + ASCT. Those patients who were FDG PET
positive after ICE but became FDG PET negative after GVD
had similar outcomes as those who were PET negative after ICE.70
PET/CT Before and After Allogeneic Stem Cell
Transplantation for Relapsed HL
A number of studies demonstrate a high prognostic value of
pretransplant FDG PET/CT before allogeneic stem cell transplan-
tation with reduced intensity.71–73 Two studies indicate that after
allogeneic stem cell transplantation FDG PET/CT may have a role
in guiding the use of donor lymphocyte infusions.74,75
PET/CT in the Setting of Novel Agents
Including Immunotherapy
In contrast to the wealth of studies documenting the value of
FDG PET/CT in first- and second-line treatment, relatively few
data are available to document the value of FDG PET/CT in the
management of relapsed and refractory (r/r) HL outside the trans-
plant setting. The phase II study of brentuximab vedotin in r/r HL
showed response in 75% of all patients, including 34% with a CR
as best response. The analyses of PFS showed a striking difference
in outcomes between patients with PR and CR as best response.
All patients had a PET/CT scan after 4 of 16 planned treatment
cycles, and the vast majority of patients who achieved a negative
FDG PET did so at this point relatively early during treatment.
For the 34% of patients who became FDG PET negative, median
PFS had not been reached at the time of the most recent follow-up,
more than 5 years after the last treatment given, whereas re-
sponders who remained PET positive (PR as best response) had
median PFS of approximately 8 months.76,77
The anti-PD1 checkpoint inhibitors nivolumab and
pembrolizumab have overall response rates comparable to those
of brentuximab vedotin in r/r HL, but apparently lower CR
rates.78,79 Based on experience from the use of checkpoint inhibi-
tors in solid tumors80 and on casuistic reports in the lymphoma set-
ting, much attention has been given to the phenomenon of structural
and/or metabolic tumor flare in a later responding patient. Such
pseudoprogression can mimic real progression, and this is a chal-
lenge because those patients who experience pseudoprogression
may actually be the ones who have the longest benefit from treat-
ment.80 Two different articles have been published with proposals
for adjustments of the response assessment criteria from the Lugano
classification,22 both with the ambition to meet the new challenges
posed by pseudoprogression.81,82 A simple and practical way to
avoid the potential challenges of pseudoprogression during immu-
notherapy for HL is to refrain from scanning the patients early dur-
ing treatment unless clearly indicated by symptoms and/or signs
indicating treatment failure.
FDG PET/CT in the Follow-up Setting
The largest study to date of routine surveillance imaging in
the follow-up setting included a subcohort of HL patients. The
study showed little or no benefit from routine imaging. A study
of FDG PET/CT surveillance in 161 Danish HL patients resul-
ted in 45% of relapses being detected subclinically, but at the
www.journalppo.com 219
Hutchings
price of high false-positive rates and correspondingly low positive
predictive values.83
CONCLUSIONS
Apart from the introduction of novel and potent targeted drugs
to treat HL, the introduction of FDG PET/CT is the most impor-
tant improvement of the management of HL in the last 2 decades.
18-Fluoro-2-deoxy-D-glucose PET/CT enables more accurate
staging, enabling more refined risk stratification and a better
basis for selection of therapy and better definition of the involved
nodes for subsequent conformal radiotherapy, but also an inherent
tendency to cause upstaging. Upstaging means a higher treat-
ment burden, and this is particularly undesirable in a disease
where late treatment-related mortality and morbidity are promi-
nent challenges. Early response assessment with FDG PET accu-
rately stratifies patients into responders with a good prognosis and
nonresponders who generally have a poorer prognosis. The high
prognostic value of early interim FDG PET is the basis for a large
number of trials with PET response–adapted therapy, which have
been performed and reported in the last 10 years. These trials have
demonstrated that the overall treatment burden (both duration and
dose intensity) can be reduced safely in patients who are early
FDG PET negative, while at the same time outcomes can be im-
proved by escalating treatment as a consequence of a positive
FDG PET/CT scan. 18-Fluoro-2-deoxy-D-glucose PET/CT is rec-
ommended not only as standard of care for staging and early treat-
ment monitoring, but also for posttreatment response assessment
and identification of a suspected relapse. On the contrary, FDG
PET/CT has no role in routine follow-up of patients in remission
after treatment for HL.
REFERENCES
1. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the
staging and response assessment of lymphoma: consensus of the Interna-
tional Conference on Malignant Lymphomas Imaging Working Group.
J Clin Oncol. 2014;32:3048–3058.
2. Warburg O. Über den Stoffwechsel der Tumoren: arbeiten aus dem Kaiser
Wilhelm-Institut für Biologie, Berlin-Dahlem. Berlin, Germany: Springer;
1926.
3. Yamamoto T, Seino Y, Fukumoto H, et al. Over-expression of facilitative
glucose transporter genes in human cancer. Biochem Biophys Res Commun.
1990;170:223–230.
4. Aloj L, Caraco C, Jagoda E, et al. Glut-1 and hexokinase expression: rela-
tionship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells
in culture. Cancer Res. 1999;59:4709–4714.
5. Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on
Hodgkin's Disease Staging Classification. Cancer Res. 1971;31:1860–1861.
6. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened
to discuss the evaluation and staging of patients with Hodgkin's disease:
Cotswolds meeting. J Clin Oncol. 1989;7:1630–1636.
7. Paul R. Comparison of fluorine-18-2-fluorodeoxyglucose and gallium-67
citrate imaging for detection of lymphoma. J Nucl Med. 1987;28:288–292.
8. Jerusalem G, Warland V, Najjar F, et al. Whole-body 18F-FDG PET for the
evaluation of patients with Hodgkin's disease and non-Hodgkin's lym-
phoma. Nucl Med Commun. 1999;20:13–20.
9. Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role of whole-
body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET in nodal staging. Ra-
diology. 1997;203:795–800.
10. Delbeke D, Martin WH, Morgan DS, et al. 2-deoxy-2-[F-18]fluoro-D-glu-
cose imaging with positron emission tomography for initial staging of
Hodgkin's disease and lymphoma. Mol Imaging Biol. 2002;4:105–114.
11. Hutchings M, Loft A, Hansen M, et al. Position emission tomography with
or without computed tomography in the primary staging of Hodgkin's lym-
phoma. Haematologica. 2006;91:482–489.
220 www.journalppo.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Cancer Journal • Volume 24, Number 5, September/October 2018
12. Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for evaluation of
bone marrow infiltration in staging of lymphoma: a meta-analysis. J Nucl
Med. 2005;46:958–963.
13. El-Galaly TC, d'Amore F, Mylam KJ, et al. Routine bone marrow biopsy
has little or no therapeutic consequence for positron emission tomogra-
phy/computed tomography–staged treatment-naive patients with Hodgkin
lymphoma. J Clin Oncol. 2012;30:4508–4514.
14. Jerusalem G, Beguin Y, Fassotte MF, et al. Whole-body positron emission
tomography using 18F-fluorodeoxyglucose compared to standard proce-
dures for staging patients with Hodgkin's disease. Haematologica. 2001;
86:266–273.
15. Weihrauch MR, Re D, Bischoff S, et al. Whole-body positron emission to-
mography using 18F-fluorodeoxyglucose for initial staging of patients with
Hodgkin's disease. Ann Hematol. 2002;81:20–25.
16. Barrington SF, Kirkwood AA, Franceschetto A, et al. PET-CT for staging
and early response: results from the Response-Adapted Therapy in Ad-
vanced Hodgkin Lymphoma study. Blood. 2016;127:1531–1538.
17. Ansquer C, Hervouët T, Devillers A, et al. 18-F FDG-PET in the staging of
lymphocyte-predominant Hodgkin's disease. Haematologica. 2008;93:
128–131.
18. Maraldo MV, Brodin NP, Vogelius IR, et al. Risk of developing cardiovas-
cular disease after involved node radiotherapy versus mantle field for
Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;83:1232–1237.
19. Hodgson DC. Late effects in the era of modern therapy for Hodgkin lym-
phoma. Hematology Am Soc Hematol Educ Program. 2011;2011:323–329.
20. Hutchings M, Loft A, Hansen M, et al. Clinical impact of FDG-PET/CT in
the planning of radiotherapy for early-stage Hodgkin lymphoma. Eur J
Haematol. 2007;78:206–212.
21. Girinsky T, Ghalibafian M, Bonniaud G, et al. Is FDG-PET scan in patients
with early stage Hodgkin lymphoma of any value in the implementation of
the involved-node radiotherapy concept and dose painting? Radiother
Oncol. 2007;85:178–186.
22. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin
lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–3068.
23. Eichenauer DA, Aleman BMP, Andre M, et al. Hodgkin lymphoma: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2018.
24. Hoppe RT, Advani RH, Ai WZ, et al. NCCN guidelines insights: Hodgkin
lymphoma, version 1.2018. J Natl Compr Canc Netw. 2018;16:245–254.
25. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage
migration and new diagnostic techniques as a source of misleading statistics
for survival in cancer. N Engl J Med. 1985;312:1604–1608.
26. Cottereau AS, Versari A, Loft A, et al. Prognostic value of baseline meta-
bolic tumor volume in early-stage Hodgkin lymphoma in the standard
arm of the H10 trial. Blood. 2018;131:1456–1463.
27. Moskowitz AJ, Schoder H, Gavane S, et al. Prognostic significance of base-
line metabolic tumor volume in relapsed and refractory Hodgkin lym-
phoma. Blood. 2017;130:2196–2203.
28. Akhtari M, Milgrom SA, Pinnix CC, et al. Reclassifying patients with
early-stage Hodgkin lymphoma based on functional radiographic markers
at presentation. Blood. 2018;131:84–94.
29. Hutchings M, Barrington SF. PET/CT for therapy response assessment in
lymphoma. J Nucl Med. 2009;50(suppl 1):21S–30S.
30. Rankin SC. Assessment of response to therapy using conventional imaging.
Eur J Nucl Med Mol Imaging. 2003;30(suppl 1):S56–S64.
31. Canellos GP. Residual mass in lymphoma may not be residual disease.
J Clin Oncol. 1988;6:931–933.
32. Hutchings M, Mikhaeel NG, Fields PA, et al. Prognostic value of interim
FDG-PET after two or three cycles of chemotherapy in Hodgkin lym-
phoma. Ann Oncol. 2005;16:1160–1168.
33. Hutchings M, Kostakoglu L, Zaucha JM, et al. In vivo treatment sensitivity
testing with positron emission tomography/computed tomography after one
cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol. 2014;32:
2705–2711.
34. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim
positron emission tomography for Hodgkin lymphoma treatment outcome
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Cancer Journal • Volume 24, Number 5, September/October 2018
is confirmed using the interpretation criteria of the Deauville five-point
scale. Haematologica. 2014;99:1107–1113.
35. Cerci JJ, Pracchia LF, Linardi CC, et al. 18F-FDG PET after 2 cycles of
ABVD predicts event-free survival in early and advanced Hodgkin lym-
phoma. J Nucl Med. 2010;51:1337–1343.
36. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of che-
motherapy predicts treatment failure and progression-free survival in Hodg-
kin lymphoma. Blood. 2006;107:52–59.
37. Gallamini A, Rigacci L, Merli F, et al. The predictive value of positron
emission tomography scanning performed after two courses of standard
therapy on treatment outcome in advanced stage Hodgkin's disease.
Haematologica. 2006;91:475–481.
38. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-
deoxy-D-glucose positron emission tomography is prognostically superior
to international prognostic score in advanced-stage Hodgkin's lymphoma:
a report from a joint Italian-Danish study. J Clin Oncol. 2007;25:3746–3752.
39. Meignan M, Gallamini A, Meignan M, et al. Report on the first interna-
tional workshop on interim-PET scan in lymphoma. Leuk Lymphoma.
2009;50:1257–1260.
40. Biggi A, Gallamini A, Chauvie S, et al. International validation study for
interim PET in ABVD-treated, advanced-stage Hodgkin lymphoma: inter-
pretation criteria and concordance rate among reviewers. J Nucl Med.
2013;54:683–690.
41. Biggi A, Bergesio F, Chauvie S, et al. Concomitant semi-quantitative and
visual analysis improves the predictive value on treatment outcome of in-
terim 18F-fluorodeoxyglucose/positron emission tomography in advanced
Hodgkin lymphoma. Q J Nucl Med Mol Imaging. 2017.
42. Markova J, Kahraman D, Kobe C, et al. Role of [18F]-fluoro-2-deoxy-D-
glucose positron emission tomography in early and late therapy assessment
of patients with advanced Hodgkin lymphoma treated with bleomycin,
etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and
prednisone. Leuk Lymphoma. 2012;53:64–70.
43. Simontacchi G, Filippi AR, Ciammella P, et al. Interim PET after two
ABVD cycles in early-stage Hodgkin lymphoma: outcomes following the
continuation of chemotherapy plus radiotherapy. Int J Radiat Oncol Biol
Phys. 2015;92:1077–1083.
44. Straus DJ, Johnson JL, LaCasce AS, et al. Doxorubicin, vinblastine, and
gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma:
pretreatment prognostic factors and interim PET. Blood. 2011;117:
5314–5320.
45. Rigacci L, Puccini B, Zinzani PL, et al. The prognostic value of positron
emission tomography performed after two courses (INTERIM-PET) of
standard therapy on treatment outcome in early stage Hodgkin lymphoma:
a multicentric study by the Fondazione Italiana Linfomi (FIL). Am J
Hematol. 2015;90:499–503.
46. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term
cause-specific mortality of patients treated for Hodgkin's disease. J Clin
Oncol. 2003;21:3431–3439.
47. Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed
therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015;372:
1598–1607.
48. Andre MPE, Girinsky T, Federico M, et al. Early positron emission tomog-
raphy response-adapted treatment in stage I and II Hodgkin lymphoma: fi-
nal results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol.
2017;35:1786–1794.
49. Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in
early positron emission tomography–negative stage I/II Hodgkin lym-
phoma is associated with an increased risk of early relapse: clinical results
of the preplanned interim analysis of the randomized EORTC/LYSA/FIL
H10 trial. J Clin Oncol. 2014;32:1188–1194.
50. Engert A, Diehl V, Franklin J, et al. Escalated-dose BEACOPP in the treat-
ment of patients with advanced-stage Hodgkin's lymphoma: 10 years of fol-
low-up of the GHSG HD9 study. J Clin Oncol. 2009;27:4548–4554.
51. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by in-
terim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med.
2016;374:2419–2429.
52. Trotman J, Foss+Ñ A, Federico M, et al. Response-adjusted therapy for ad-
vanced Hodgkin lymphoma (RATHL) trial: longer follow up confirms
© 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Improvements in Imaging of Hodgkin Lymphoma
efficacy of de-escalation after a negative interim PET scan (CRUK/07/033).
Hematol Oncol. 2017;35(S2):65–67.
53. Gallamini A, Tarella C, Viviani S, et al. Early chemotherapy intensification
with escalated BEACOPP in patients with advanced-stage Hodgkin lym-
phoma with a positive interim positron emission tomography/computed to-
mography scan after two ABVD Cycles: long-term results of the GITIL/
FIL HD 0607 trial. J Clin Oncol. 2018;36:454–462.
54. Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients
with advanced-stage Hodgkin's lymphoma (HD18): final results of an
open-label, international, randomised phase 3 trial by the German Hodgkin
Study Group. Lancet. 2018;390:2790–2802.
55. Borchmann P, Goergen H, Kobe C, et al. Early interim PET in patients with
advanced-stage Hodgkin's lymphoma treated within the phase 3
GHSG HD18 study. Blood. 2017;130(suppl 1):737.
56. Casasnovas O, Brice P, Bouabdallah R, et al. Randomized phase III study
comparing an early PET driven treatment de-escalation to a not PET-mon-
itored strategy in patients with advanced stages Hodgkin lymphoma: final
analysis of the AHL2011 LYSA study. JCO. 2018;36(15_suppl):7503.
57. Kobe C, Dietlein M, Franklin J, et al. Positron emission tomography has a
high negative predictive value for progression or early relapse for patients
with residual disease after first-line chemotherapy in advanced-stage Hodg-
kin lymphoma. Blood. 2008;112:3989–3994.
58. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy
and PET-guided radiotherapy in patients with advanced stage Hodgkin's
lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority
trial. The Lancet. 2012;379:1791–1799.
59. Savage KJ, Connors JM, Villa DR, et al. Advanced stage classical Hodgkin
lymphoma patients with a negative PET-scan following treatment with
ABVD have excellent outcomes without the need for consolidative radio-
therapy regardless of disease bulk at presentation. Blood. 2015;126:579.
60. Zijlstra JM, Lindauer-van der Werf G, Hoekstra OS, et al. 18F-fluoro-
deoxyglucose positron emission tomography for post-treatment evaluation of
malignant lymphoma: a systematic review. Haematologica. 2006;91:522–529.
61. Terasawa T, Nihashi T, Hotta T, et al. 18F-FDG PET for posttherapy assess-
ment of Hodgkin's disease and aggressive non-Hodgkin's lymphoma: a sys-
tematic review. J Nucl Med. 2008;49:13–21.
62. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for
malignant lymphoma. J Clin Oncol. 2007;25:579–586.
63. Brepoels L, Stroobants S, De Wever W, et al. Hodgkin lymphoma: response
assessment by revised International Workshop Criteria. Leuk Lymphoma.
2007;48:1539–1547.
64. Spaepen K, Stroobants S, Dupont P, et al. Can positron emission tomogra-
phy with [(18)F]-fluorodeoxyglucose after first-line treatment distinguish
Hodgkin's disease patients who need additional therapy from others in
whom additional therapy would mean avoidable toxicity? Br J Haematol.
2001;115:272–278.
65. Weihrauch MR, Re D, Scheidhauer K, et al. Thoracic positron emission
tomography using 18F-fluorodeoxyglucose for the evaluation of residual
mediastinal Hodgkin disease. Blood. 2001;98:2930–2934.
66. Bröckelmann PJ, Müller H, Casasnovas O, et al. Risk factors and a prognos-
tic score for survival after autologous stem-cell transplantation for relapsed
or refractory Hodgkin lymphoma. Ann Oncol. 2017;28:1352–1358.
67. Mocikova H, Pytlik R, Markova J, et al. Pre-transplant positron emission to-
mography in patients with relapsed Hodgkin lymphoma. Leuk Lymphoma.
2011;52:1668–1674.
68. Smeltzer JP, Cashen AF, Zhang Q, et al. Prognostic significance of FDG-
PET in relapsed or refractory classical Hodgkin lymphoma treated with
standard salvage chemotherapy and autologous stem cell transplantation.
Biol Blood Marrow Transplant. 2011;17:1646–1652.
69. Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplantation func-
tional imaging predicts outcome following autologous stem cell transplan-
tation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116:
4934–4937.
70. Moskowitz AJ, Schöder H, Yahalom J, et al. PET-adapted sequential sal-
vage therapy with brentuximab vedotin followed by augmented ifosamide,
carboplatin, and etoposide for patients with relapsed and refractory
Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase
2 study. Lancet Oncol. 2015;16:284–292.
www.journalppo.com 221
Hutchings
71. Reyal Y, Kayani I, Bloor AJC, et al. Impact of pretransplantation
¹⁸F-fluorodeoxyglucose-positron emission tomography on
survival outcomes after T Cell–depleted allogeneic transplantation
for Hodgkin lymphoma. Biol Blood Marrow Transplant. 2016;22:1234–1241.
72. Marani C, Raiola AM, Morbelli S, et al. Haploientical transplants with
post-transplant cyclophosphamide for relapsed or refractory Hodgkin lym-
phoma: the role of comorbidity index and pretransplant positron emission
tomography. Biol Blood Marrow Transplant. 2018; S1083-8791(18)30414-2.
73. Dodero A, Crocchiolo R, Patriarca F, et al. Pretransplantation [18-F]
fluorodeoxyglucose positron emission tomography scan predicts outcome
in patients with recurrent Hodgkin lymphoma or aggressive non-Hodgkin
lymphoma undergoing reduced-intensity conditioning followed by alloge-
neic stem cell transplantation. Cancer. 2010;116:5001–5011.
74. Lambert JR, Bomanji JB, Peggs KS, et al. Prognostic role of PET scanning
before and after reduced-intensity allogeneic stem cell transplantation for
lymphoma. Blood. 2010;115:2763–2768.
75. Hart DP, Avivi I, Thomson KJ, et al. Use of 18F-FDG positron emission
tomography following allogeneic transplantation to guide adoptive immuno-
therapy with donor lymphocyte infusions. Br J Haematol. 2005;128:824–829.
76. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating
durable responses from a pivotal phase 2 study of brentuximab vedotin in
patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;
126:2736.
222 www.journalppo.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Cancer Journal • Volume 24, Number 5, September/October 2018
77. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2
study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.
Blood. 2015;125:1236.
78. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and
safety of pembrolizumab for relapsed/refractory classic Hodgkin lym-
phoma. J Clin Oncol. 2017;35:2125–2132.
79. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory
classic Hodgkin lymphoma after failure of autologous hematopoietic cell
transplantation: extended follow-up of the multicohort single-arm phase
II CheckMate 205 trial. J Clin Oncol. 2018;36:1428–1439.
80. Kurra V, Sullivan RJ, Gainor JF, et al. Pseudoprogression in cancer im-
munotherapy: rates, time course and patient outcomes. JCO. 2016;34
(15_suppl):6580.
81. Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano classi-
fication lymphoma response criteria in the era of immunomodulatory ther-
apy. Blood. 2016;128:2489.
82. Younes A, Hilden P, Coiffier B, et al. International Working Group consen-
sus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol.
2017;28:1436–1447.
83. El-Galaly TC, Mylam KJ, Brown P, et al. Positron emission tomography/
computed tomography surveillance in patients with Hodgkin lymphoma
in first remission has a low positive predictive value and high costs.
Haematologica. 2012;97:931–936.
© 2018 Wolters Kluwer Health, Inc. All rights reserved.