Review Article

Immunotherapy and the Role of Imaging

Brett W. Carter, MD ; Priya R. Bhosale, MD; and Wei T. Yang, MD

Significant advances in the genetic and molecular characterization of cancer have led to the development of effective immunothera-
pies. These therapeutics help the host immune system recognize cancer as foreign, promote the immune system, and relieve the inhi-
bition that allows growth and spread of tumors. Experience with various immunotherapies, particularly the immunomodulatory
monoclonal antibody ipilimumab, has demonstrated that unique patterns of response may be encountered that cannot be adequately
captured by traditional response criteria, such as the World Health Organization (WHO) criteria and Response Evaluation Criteria in
Solid Tumors (RECIST), which have been used primarily with cytotoxic chemotherapies. In response to these observations, several
novel response criteria have been developed to evaluate patients who receive immunotherapy, including immune-related response
criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST). These criteria are typically used in conjunction
with RECIST version 1.1 in the clinical trial setting, because approval of new therapeutics by the US Food and Drug Administration
relies on the responses derived from RECIST version 1.1. Finally, a wide variety of immune-related adverse events may affect patients
who receive immunotherapy, many of which can be identified on imaging studies such as computed tomography, magnetic resonance
imaging, and 2-deoxy-2-(fluorine-18)fluoro-D-glucose–positron emission tomography/computed tomography. In this review, the
authors present the role of imaging in the evaluation of patients treated with immunotherapy, including the background and applica-
tion of irRC, irRECIST, and iRECIST; the imaging of immune-related adverse events; and future directions in advanced imaging of
immunotherapy. Cancer 2018;124:2906-22. V C 2018 American Cancer Society.

KEYWORDS: imaging, immune Response Evaluation Criteria in Solid Tumors (iRECIST), immune-related response criteria (irRC),
immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), immunotherapy, response criteria.

INTRODUCTION
Significant advances in the genetic and molecular characterization of cancer have led to the development of effective
immunotherapies, which assist the host immune system in recognizing cancer as foreign, stimulate the immune system,
and relieve the inhibition that allows growth and spread of tumors. In contrast to traditional chemotherapy, which mainly
targets rapidly dividing cells, and targeted therapies, which interfere with important molecular events in cancer cells that
drive growth and invasion, immunotherapy attempts to assist in the recognition of cancer as foreign by the host immune
system, stimulate the immune system, and relieve the inhibition that allows tumor growth and spread. Immunotherapy is
described as either active or passive, depending on its interaction with the host immune system and the type of response
elicited. For instance, the active immune response involves humoral and/or cell-mediated immunity, whereas the passive
immune response requires no activation of the immune system and involves passively infused, preformed antitumor
immunoglobulins to tumor-associated antigens.
As the treatment options for cancer continue to advance, the development of imaging criteria for appropriately
assessing response to therapy is critical. Increased use of immunotherapy has demonstrated a wide variety of imaging fea-
tures and patterns of disease that are imperative to understand when assessing patients.1-3 Extensive experience with ipili-
mumab, an immunomodulatory monoclonal antibody, has demonstrated that several unique responses may be observed
during the course of treatment with immunotherapies that are not adequately captured by traditional response criteria like
the World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST).4 For
instance, in contrast to conventional response criteria, a transient increase followed by a subsequent decrease may be
encountered as treatment response (so called pseudoprogression). However, delayed or subsequent regression has been
demonstrated in only about 10% of patients with melanoma.4 Because of these observations, several response criteria have
been developed to evaluate patients who receive immunotherapy, including immune-related response criteria (irRC),
immune-related RECIST (irRECIST), and immune RECIST (iRECIST).4,5 With the increasing use of immunotherapy,
it is becoming easier to recognize numerous immune-related adverse events, such as colitis, hepatitis, pneumonitis, and
various endocrine toxicities.2,6 It is important for radiologists and other providers to be familiar with the imaging
Corresponding author: Brett W. Carter, MD, Department of Diagnostic Radiology, Section of Thoracic Imaging, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Boulevard, Unit 1478, Houston, TX 77030; bcarter2@mdanderson.org

Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas

DOI: 10.1002/cncr.31349, Received: November 16, 2017; Revised: January 30, 2018; Accepted: February 1, 2018, Published online April 19, 2018 in Wiley
Online Library (wileyonlinelibrary.com)

2906 Cancer July 15, 2018


manifestations of immune-related adverse events in
patients who are receiving immunotherapy and to distin-
guish these findings from progression of disease.
In this review, we present the role of imaging in the
evaluation of patients treated with immunotherapy,
including specific response criteria, such as irRC, irRE-
CIST, and iRECIST, and the imaging of immune-related
adverse events.
EVALUATION OF TREATMENT RESPONSE
Investigators traditionally have relied on response criteria
to evaluate the effectiveness of chemotherapy, the most
widely used of which have been the WHO criteria and
RECIST guidelines. The WHO criteria were the first
standardized response criteria but were limited by several
factors.7 The original RECIST guidelines (RECIST 1.0),
published in 2000, were developed by a large, interna-
tional group of investigators to standardize the characteri-
zation of treatment efficacy using specific response
definitions.8 This was followed by the release of revised
RECIST criteria (RECIST 1.1) in in 2009.9 These criteria
are optimized to evaluate the cytotoxic effects of chemo-
therapeutic agents on solid tumors, and specific effects
can be identified on imaging studies usually within a few
weeks of therapy. These guidelines depend on a decrease
in the size of tumors and the absence of new lesions.1,4
Therefore, it is assumed that a significant increase in
tumor growth and/or the appearance of new lesions indi-
cates progressive disease (PD). Typically, chemotherapy is
discontinued once progressive disease (PD) is docu-
mented. A significant limitation of these traditional
response criteria is that several specific patterns of
response known to occur in patients who receive treat-
ment with other agents, such as antiangiogenic therapies
or immune therapies, are not appropriately captured. For
instance, new agents, such as cytokines, cancer vaccines,
and immunomodulatory monoclonal antibodies, may
produce a delayed response, a transient increase in size fol-
lowed by tumor shrinkage, and/or the appearance of new
lesions, which become stable, decrease, or resolve without
further treatment.4 However, only about 10% of patients
who receive immunotherapy demonstrate regression after
initial progression.4
To reflect these observations and overcome existing
limitations, many modifications have been made to tradi-
tional response criteria; however, in many instances, these
criteria have not been standardized and incorporated into
clinical trials in an organized fashion. Thus, new criteria,
such as irRC, irRECIST, and iRECIST, have been devel-
oped to assist investigators and clinicians in distinguishing
Cancer July 15, 2018
Immunotherapy and the Role of Imaging/Carter et al
between patients who are and are not responding to a par-
ticular treatment as early as possible.
Immune-Related Response Criteria
Background and development
In 2004 and 2005, a multidisciplinary group of experts
presented and analyzed their experiences with immuno-
therapy and treatment response. This group outlined sev-
eral key points: 1) Measurable antitumor activity may
take longer to manifest for immunotherapies than for tra-
ditional chemotherapy; 2) responses to immunotherapy
may occur after the identification of PD by traditional
response criteria, such as RECIST 1.1; 3) continuation of
immunotherapy may be appropriate in clinically stable
patients who have PD; 4) consideration of clinically insig-
nificant PD is recommended (such as the development of
new, small lesions in a patient with lesions that are
responding to therapy); and 5) prolonged and durable sta-
ble disease (SD) may represent effective therapy.4 An anal-
ysis of 487 patients with unresectable stage III or IV
melanoma who received treatment with ipilimumab (a
human monoclonal antibody that blocks cytotoxic T-
lymphocyte antigen-4 [CTLA-4]) in 3 multicenter, phase
2 clinical trials demonstrated 4 patterns of clinical
response, including: 1) a decrease in lesion size without
new disease, 2) SD after the completion of therapy, 3) a
delay in response after an initial increase in total tumor
burden (TTB), and 4) the appearance of new lesions
before a decrease in tumor size. The first 2 response pat-
terns were appropriately captured with conventional
response criteria, including responses in baseline lesions
without new lesions and, in some patients, SD followed
by a slow, steady decline in disease. The other 2 response
patterns were novel and included responses after an initial
increase in TTB (so-called pseudoprogression) and a
reduction in TTB during or after the appearance of new
lesion(s).4 The immune-related response criteria (irRC)
published by Wolchok et al in 2009 were based on these
observed patterns.
Principles and application
The irRC were adapted from the WHO criteria and
designed to address treatment response and recommenda-
tions for imaging follow-up of patients who received
immunotherapy. There are many differences between
conventional response criteria, such as RECIST 1.1, and
irRC (Table 1). For instance, the irRC do not specifically
address which imaging modalities should be used in the
evaluation of treatment response, and anatomic and com-
bined anatomic and metabolic methods of assessment are
2907
 TABLE 1. Comparison of Response Evaluation Criteria in Solid Tumors (RECIST), Immune-Related Response Criteria, Immune-Related RECIST,
and Immune RECIST

2908
Variable RECIST 1.1 irRC irRECIST iRECIST

Imaging modality CT, MRI, FDG-PET, chest radiography;a Not specifically mentioned; CT, MRI, CT, MRI, FDG-PET, chest radiography;a CT, MRI, FDG-PET, chest radiography;a
clinical measurements documented FDG-PET may be used; clinical clinical measurements documented by clinical measurements documented by
Review Article

by photography with rulerb
No. of target Two per organ, 5 total
lesions
Measurable size Solid-organ lesions 10 mm in long axis,
15 mm in short axis for lymph nodesc
Measurement Unidimensional measurement
parameters
Tumor burden Sum of the greatest dimensions of all
target lesions
Unmeasurable 1. Measurable lesions not selected as
lesions target lesions
2. Unmeasurable disease, including lesions
that are too small to measure (<10 mm
in long axis for solid-organ lesions or <15
mm in short axis for lymph nodes)
3. Other types of lesions that are difficult to
measure in a reproducible manner include:
bone metastases, leptomeningeal metas-
tases, malignant ascites, pleural or peri-
cardial effusions, ascites, inflammatory
breast disease, lymphangitic
carcinomatosis, ill-defined abdominal
masses, skin lesions, etc
New lesions Constitutes PD
measurements documented by
photography with rulerb
Five per organ, up to 10 visceral and 5
cutaneous
5 3 5 mm
Bidimensional measurements
Sum of the products of the 2 greatest
perpendicular dimensions of
all target lesions
Not specifically defined; nontarget lesions
derived from irRC include: lymphangitic
carcinomatosis, skin involvement
in breast cancer, abdominal masses
that can be palpated but not measured
Does not constitute PD automatically;
incorporated into total tumor burden
photography with rulerb
Two per organ, 5 total
Solid-organ lesions 10 mm in long axis;
15 mm in short axis for lymph nodesc
Unidimensional measurement
Sum of the greatest dimensions of all
target lesions
Follow definitions from RECIST 1.1
Does not constitute PD automatically;
incorporated into total measured
tumor burden
photography with rulerb
Two per organ, 5 total
Solid-organ lesions 10 mm in long axis, 15
mm in short axis for lymph nodesc
Unidimensional measurement
Sum of the greatest dimensions of all
target lesions
Follow definitions from RECIST 1.1
Results in iUPD; iCPD only achieved if
additional new lesions are present on
the subsequent time point or there is an
increase in the size of previous new lesions
(5 mm for the sum of new
target lesions or any increase in new
nontarget lesions)

Abbreviations CT, computed tomography; iCPD, immune RECIST-confirmed progressive disease; irRC, immune-related response criteria; iUPD, immune RECIST-unconfirmed progressive disease; MRI, magnetic
resonance imaging; PD, progressive disease; PET-FDG, positron emission tomography–2-deoxy-2-(fluorine-18)fluoro-D-glucose; RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
a
Target lesions require a size of 20 mm on chest radiography according to RECIST.

Cancer
b
Cutaneous lesions are included in potential tumor burden; therefore, clinical measurements theoretically may be allowed.
c
Sizes are confirmed on newer generation multidetector imaging. Other parameters are listed for nonhelical CT (10 mm slice thickness) and chest radiography.

July 15, 2018

 Immunotherapy and the Role of Imaging/Carter et al

TABLE 2. Response Assessment and New Lesions in Immune-Related Response Criteria

irRC Category Description

Complete response (irCR)
Partial response (irPR)
Stable disease (irSD)
Progressive disease (irPD)
New measureable lesions
New nonmeasurable lesions
Complete disappearance of all lesions; confirmation by repeat, consecutive assessment 4 wks from first
documentation
Decrease in tumor burden 50% relative to baseline; confirmation by repeat, consecutive assessment 4 wks from
first documentation
Does not meet criteria for irCR or irPR, in the absence of irPD
Increase in tumor burden 25% relative to nadir (minimum recorded tumor burden); confirmation by repeat,
consecutive assessment 4 wks from first documentation
Incorporated into tumor burden
New, nonmeasurable lesions at follow-up time points are not added to total tumor burden and do not define
progression but preclude irCR; nontarget, unequivocal progression contributes to irCR but not irPD

Abbreviations: irRC, immune-related response criteria.

Figure 1. Images of pseudoprogression from a woman aged 64 years who had adenocarcinoma of the right lower lobe and
received radiation therapy and immunotherapy are shown. (A) A contrast-enhanced, axial computed tomography (CT) scan
obtained at baseline reveals a right lower lobe nodule (arrow). Note the small right pleural effusion (asterisk). (B) A follow-up
contrast-enhanced, axial CT scan obtained 6 weeks later shows an interval increase in the size of the nodule (arrow) and an
increase in the size of the right pleural effusion (asterisk). (C) Another follow-up contrast-enhanced, axial CT obtained 6 weeks
later reveals an interval decrease in the size of the nodule (arrow) and a slight increase in the size of the right pleural effusion
(asterisk). With novel response criteria designed for use with immunotherapy, new lesions or an increase in tumor burden must
be confirmed by repeat imaging at a minimum of 4 weeks later to constitute progression.

Cancer July 15, 2018 2909

Review Article

Figure 2. Images of pseudoprogression from a woman aged 66 years who received immunotherapy for lung cancer are shown.
(A) A contrast-enhanced, axial computed tomography (CT) scan at baseline demonstrates a normal-sized, right paratracheal
lymph node (arrow). (B) A follow-up contrast-enhanced, axial CT scan obtained 6 weeks later reveals a marked interval increase
in the size of the right paratracheal lymph node (arrow) and the presence of additional, smaller lymph nodes in the right prevas-
cular mediastinum (arrowhead). (C) Another follow-up contrast-enhanced, axial CT scan obtained 6 weeks later shows a marked
interval decrease in the size of the right paratracheal lymph node (arrow) and disappearance of the other lymph nodes in the
right prevascular mediastinum.

frequently used interchangeably in clinical trials. How-
ever, in contrast to RECIST 1.1, only anatomic measure-
ments are considered. For all cases, the TTB, defined as
the sum of the products of the 2 greatest perpendicular
dimensions (SPD) of all index lesions (measured in
mm2), is calculated at baseline and at all subsequent time
points. Target lesions must measure 5 3 5 mm, and up
to 5 may be selected per organ (up to 10 lesions involving
visceral organs and 5 cutaneous lesions). At subsequent
time points, the TTB is calculated by the addition of the
SPD of all target lesions and the SPD of any new measur-
able lesions (TTB 5 SPDindex lesions 1 SPDnew measur-
able lesions). This differs significantly from conventional
response criteria, which consider all new lesions as PD.
Once the TTB is calculated, an overall response cate-
gory is assigned to each case based on changes between
time point assessments. These response categories include
a complete response (irCR), a partial response (irPR), SD
(irSD), and PD (irPD) (Table 2). The TTB must increase
by 25% and must be confirmed by repeat imaging at a
minimum of 4 weeks later to constitute definitive irPD.
New lesions or a perceived increase in TTB because of
pseudoprogression can result from immune cell recruit-
ment to sites of microscopic disease (Figs. 1 and 2). In
irRC, all patients who have an irCR, irPR, and irPD must
have repeat imaging performed at a minimum of 4 weeks
later for confirmation if they are clinically stable; however,
follow-up with observation alone may not be appropriate

2910 Cancer July 15, 2018

 Immunotherapy and the Role of Imaging/Carter et al

TABLE 3. Response Assessment and New Lesions in Immune-Related Response Evaluation Criteria in Solid
Tumors

irRC Category Description

Complete response (irCR)
Partial response (irPR)
Stable disease (irSD)
Progressive disease (irPD)
New measureable lesions
New nonmeasurable lesions
Complete disappearance of all measurable and nonmeasurable lesions; lymph nodes must decrease to <10 mm
in the short axis; confirmation is not mandatory
Decrease 30% in TMTB relative to baseline; nontarget lesions are irNN; no unequivocal progression of new
nonmeasurable lesions
Failure to meet criteria for irCR or irPR in the absence of irPD
Minimum 20% increase and minimum 5-mm absolute increase in TMTB compared with nadir or irPD for
nontarget or new nonmeasurable lesions; confirmation of progression is recommended a minimum of 4 wks
after the first irPD assessment
Greatest dimensions of new measurable, nonlymph node lesions and short axes of new measurable lymph nodes
will be recorded and added to the TMTB at follow-up
All new lesions not selected as new measurable lesions are considered new nonmeasurable lesions and are
followed qualitatively; only a massive and unequivocal progression of new nonmeasurable lesions leads to
an overall assessment of irPD for the time point; persisting new unmeasurable lesions prevent irCR

Abbreviations: irRC, immune-related response criteria; irNN, irNon-CR/Non-PD; TMTB, total measured tumor burden.

for those who have a rapid decline in performance status.
The response of patients who have irSD, particularly those
with a slowly declining tumor burden (25% from base-
line at the last tumor assessment), is considered clinically
meaningful, because they exhibit an objectively measur-
able reduction in TTB without reaching the 50% thresh-
old that defines irPR. In addition, it is recommended
that, after the completion of therapy, an evaluation of
treatment response should be made with 2 consecutive
follow-up imaging studies at least 4 weeks apart because
of the potential for a delayed response.
ipilimumab for melanoma. Those authors demonstrated
that unidimensional measurements simulating RECIST
1.1 were more reproducible compared with the bidimen-
sional measurements of irRC.5 The group recommended
that the number of targets could be reduced to up to 2
per organ and up to 5 in total, as defined in RECIST
1.1, and proposed the use of unidimensional measure-
ments to assess response to immunotherapy in solid
tumors given their relative simplicity, higher reproduc-
ibility, and high concordance with the bidimensional
measurements of irRC.5

Limitations Principles and application

Although the irRC introduced several advancements in
terms of assessing response in patients treated with immu-
notherapy, several limitations have been described. For
instance, the irRC provide no guidance regarding the num-
ber of lesions that should be included, and assessing a rela-
tively large number of lesions per organ could be relatively
time consuming in patients with extensive disease.2,10 In
addition, there is no specific guidance regarding the assess-
ment of lymph node disease. The reproducibility of bidi-
mensional assessment also is lower than that of
unidimensional assessment. Finally, although nontarget
unequivocal progression contributes to irCR based on the
initial description by Wolchok and colleagues,4 it does not
do so with respect to irPD; however, this was not used in
the majority of studies that applied the irRC.
Immune-Related RECIST
Background and development
Nishino and colleagues evaluated the impact of reducing
the number of target lesions and using unidimensional
measurements to assess patients who received
The irRECIST are very similar to RECIST 1.1 in terms
of guidance regarding the selection of imaging modalities,
definitions of measureable and unmeasurable disease, and
criteria for selecting target and nontarget lesions.11 For
example, target lesions may include nonlymph node
lesions measuring 10 mm in the long axis or lymph
nodes measuring 15 mm in the short axis. As in
RECIST 1.1, up to 5 total target lesions may be selected
with a maximum of 2 per organ, and the measurements of
these lesions are recorded as the total measured tumor bur-
den (TMTB). Nontarget lesions may include measurable
lesions not selected as target lesions, sites of nonmeasur-
able disease, and lesions that may be difficult to measure
in a reproducible manner, such as bone lesions, leptome-
ningeal metastases, inflammatory breast disease, malignant
ascites, pleural or pericardial effusions, and lymphangitic
carcinomatosis. It is generally recommended that previ-
ously treated lesions should not be selected as target lesions
unless local progression has been documented.
A significant difference between irRECIST and
RECIST 1.1 and other response criteria is the method by

Cancer July 15, 2018 2911

Review Article

TABLE 4. Response Assessment and New Lesions in Immune Response Evaluation Criteria in Solid Tumors

iRECIST Category Description

Complete response (iCR) Resolution of all lesions, confirmed 4 wks

Partial response (iPR)
Stable disease (iSD)
Unconfirmed progressive
disease (iUPD)
Confirmed progressive
disease (iCPD)
New lesions
Decrease 30% in tumor burden compared with baseline in the absence of any new lesion or progression of nontarget
lesions
Neither PR or PD in the absence of any new lesion or progression of nontarget lesions
Increase 20% in tumor burden from nadir, progression of nontarget lesions, or new lesions; iUPD requires confirmation,
which is done on the basis of observing either a further increase in size (or in the number of new lesions) in the lesion
category in which progression was first identified (target or nontarget disease) or progression (defined by RECIST 1.1)
in lesion categories that had not previously met RECIST 1.1 progression criteria; progression is confirmed in the target
lesion category if the next imaging assessment after iUPD (4-8 wks later) confirms a further increase in sum of
measures of target disease from iUPD, with an increase of at least 5 mm
Progressive disease is confirmed (iCPD) if the next imaging assessment, done 4-8 wks after iUPD, confirms additional
new lesions, further increase in previous new lesion size (sum of measures increase in new target lesion 5 mm or
any increase for new nontarget lesions), or further increase in existing target or nontarget lesions from iUPD
Assessed according to RECIST 1.1 guidelines but recorded separately and not included in the sum of lesions for target
lesions identified at baseline; new lesions constitute iUPD; iCPD is only achieved if additional new lesions appear or
there is an increase in size of new lesions (5 mm for the sum of new target lesions or any increase in new nontarget
lesions); presence of new lesions when none have previously been recorded can also confirm iCPD

Abbreviations: iRECIST, Immune Response Evaluation Criteria in Solid Tumors; PD, progressive disease; PR, partial response; RECIST 1.1, Response Evalua-
tion Criteria in Solid Tumors, version 1.1.

which new lesions are incorporated into the assessment of Limitations

treatment response. In irRECIST, new lesions may be
characterized as measurable or unmeasurable, and those
selected as new target lesions must meet the same criteria
for inclusion as the lesions that were present at baseline.
When multiple qualifying lesions are present, it is recom-
mended that they be prioritized according to size, with the
largest lesions selected as new target lesions. In total, 5
new target lesions may be selected, with a maximum of 2
per organ. New measurable lesions that are not selected as
target lesions may be classified as new nonmeasurable
lesions and can be qualitatively followed. When new mea-
surable lesions are selected as target lesions, the greatest
dimensions of both existing and new nonlymph node tar-
get lesions and the short axis dimensions of both existing
and new lymph node target lesions constitute the TMTB.
This represents a significant difference from RECIST 1.1,
in which the appearance of new lesions is always consid-
ered PD, and therapy typically is discontinued, without a
method for following these new lesions.
Similar to irRC, the overall response categories for
irRECIST include irCR, irSD, irPR, and irPD and are
based on changes in the TMTB of measured target
lesions (baseline and new), nontarget lesion assessment,
and new nonmeasurable lesions (Table 3). These
response categories have defined thresholds for irPR and
irPD that are aligned with RECIST 1.1. For patients
with irPD and a minimal TMTB percentage increase
>20%, particularly early on in therapy (such as during
the first 12 weeks of treatment), confirmatory evaluation
may be considered.
One of the most significant limitations of irRECIST is
that these recommendations have not always been consis-
tently applied, raising concerns among clinicians and
researchers regarding the comparability of data and results
across various clinical trials. In addition, studies that dem-
onstrated the efficacy of irRECIST were performed on rel-
atively small cohorts of patients, and more detailed
evaluation of irRECIST 1.1 is still required. Finally, in
contrast to iRECIST, with irRECIST, a delayed response
after pseudoprogression that does not reach irSD will
result in a confirmation of irPD.
Immune RECIST
Background and development
In an effort to standardize and validate response criteria,
the RECIST working group evaluated data collected from
prospective clinical trials using immunotherapy and
RECIST 1.1.12 That group reported that most clinical tri-
als involving immunotherapy used RECIST 1.1 to define
primary and secondary efficacy-based endpoints and used
the irRC or modified definitions of RECIST for explor-
atory endpoints.13,14 There was significant variability in
which criteria were incorporated clinically within differ-
ent groups, raising concerns about the interpretation of
pooled data sets. In addition, most clinical trials that
applied immune-modified criteria used independent
imaging review by a commercial entity for those criteria
rather than investigator assessments. In response to the
limitations of existing response criteria and these observa-
tions, the RECIST working group developed guidelines

2912 Cancer July 15, 2018


Figure 3. Images of pneumonitis are shown. Contrast-
enhanced (A) axial and (B) coronal computed tomography
images from a man aged 21 years with melanoma who
received immunotherapy demonstrate a cryptogenic organiz-
ing pneumonia-like appearance of immune-related pneumoni-
tis with opacities in the lower lobes, appearing as central
ground-glass opacity and surrounding consolidation.
for the use of modified RECIST termed iRECIST to
ensure consistent design and data collection and to facili-
tate the ongoing collection of data from clinical trials and
ultimate validation of the guidelines.
Principles and application
The tenets of iRECIST are very similar to those of
RECIST 1.1 and irRECIST regarding the recommended
imaging modalities, definitions of measureable and
unmeasurable disease, and criteria for selecting target and
nontarget lesions.12 New lesions may be classified as target
or nontarget lesions and are evaluated as in RECIST 1.1.
However, target and nontarget lesions are recorded
Cancer July 15, 2018
Immunotherapy and the Role of Imaging/Carter et al
Figure 4. Images of pneumonitis are shown. (A) An unen-
hanced, axial computed tomography (CT) scan from a woman
aged 65 years with lung cancer who received immunotherapy
reveals diffuse opacities in the lungs. (B) An unenhanced, axial
CT scan from a woman aged 53 years with melanoma who
received immunotherapy demonstrates diffuse ground-glass
opacities superimposed on a background of interlobular septal
thickening in a crazy-paving configuration. Immune-related
pneumonitis may manifest in several ways, 1 of the most com-
mon of which is ground-glass opacity.
separately and are not included in the sum of the greatest
dimensions of all target lesions, in contrast to irRECIST.
The overall response categories for iRECIST
include iCR, iSD, iPR, unconfirmed progressive disease
(iUPD), and confirmed progressive disease (iCPD),
which are designed to allow for the identification and
improved characterization of atypical responses12 (Table
4). For target lesions, iCR, iPR, and iSD all can be
assigned after iUPD has been documented, as long as
iCPD has not been achieved. For nontarget lesions,
iUPD may be documented before iCR or when the crite-
ria for neither iCR nor iPD have been met (referred to as
non-iCPD/non-iUPD) and can be assigned several
2913
Review Article

Figure 5. Images of sarcoid-like reaction are shown. (A) A contrast-enhanced, axial computed tomography (CT) scan and (B) a fused,
axial 2-deoxy-2-(fluorine-18)fluoro-D-glucose–positron emission tomography (FDG-PET)/CT image from a man aged 64 years with
melanoma who received immunotherapy reveal new, FDG-avid, mediastinal and hilar lymphadenopathy (arrows). These lymph nodes
were subsequently biopsied without evidence of malignancy, and a clinical diagnosis of sarcoid-like reaction was made. (C) An unen-
hanced, axial CT scan and (D) and a fused, axial FDG-PET/CT study from the same patient 6 weeks later after discontinuation of ther-
apy demonstrates a marked interval decrease in the size and FDG uptake of the lymph nodes (arrows).

times, as long as iCPD has not been achieved. The
appearance of new lesions results in iUPD; however, this
requires confirmation by a further increase in size (or in
the number of new lesions) in the lesion category in
which progression was first identified (target or nontar-
get) or by progression in lesion categories that did not
previously meet RECIST 1.1 progression criteria on an
examination performed 4 to 8 weeks after iUPD. For
instance, iCPD may be assigned if additional new lesions
appear or if there is a further increase in the size of previ-
ous new lesions (5 mm for the sum of target lesions or
any increase in nontarget lesions) on the subsequent
examination. However, in the case of iUPD and no
change, if there is a decrease in tumor burden compared
with the baseline study that meets the criteria for iCR,
iPR, or iSD, then iUPD must be reached again and con-
firmed at the next time point for iCPD to have been
achieved. If there is no change in tumor size or extent,
then the time point response remains iUPD.
The RECIST working group recommends that
treatment beyond initial RECIST 1.1-defined progression
(iUPD) should/could only allow patients who are clini-
cally stable to continue on treatment until the next assess-
ment. This should be performed 4 weeks later but no
longer than 8 weeks later, to ensure that patients remain
fit for salvage therapies. All decisions regarding

2914 Cancer July 15, 2018

 Immunotherapy and the Role of Imaging/Carter et al

continuation or discontinuation of therapy should be

made by the oncologist and patient.

IMPLEMENTATION OF RESPONSE
CRITERIA IN CLINICAL TRIALS
Although these new response criteria have been developed
with principles of immunotherapy in mind, it should be
noted that the current recommendation is for them to be
used alongside RECIST 1.1 in clinical trials, because these
conventional criteria are used by the US Food and Drug
Administration for decisions regarding the approval of
therapeutics. For instance, the irRC have been used in sev-
eral clinical trials alongside RECIST 1.1 in which the
patient continues therapy beyond initial PD provided
there is investigator-assessed clinical benefit and the
patient tolerates the therapy. In this instance, the use of
the irRC is beneficial to avoid premature termination of
an effective immunotherapy with pseudoprogression when
evaluating treatment response with the imaging modalities
that are currently available. Hodi and colleagues compared
irRC and RECIST 1.1 in patients with advanced mela-
noma who received pembrolizumab and observed that
RECIST 1.1 underestimated the therapy benefit, as deter-
mined by overall survival, in 15% of patients.14 Those
authors suggested that the use of modified criteria that
permit treatment beyond initial PD determined by
RECIST 1.1 may prevent premature cessation of treat-
ment. However, atypical response rates for other tumor
entities (such as lung cancer and renal cancer) seem to be
inferior, and real progression might be more likely.
As a general limitation, all of these response criteria
are defined for anticancer response evaluation in clinical tri-
als of solid tumors with a distinct start point (baseline) and
endpoint (tumor progression). Many oncologists currently Figure 6. Images of sarcoid-like reaction are shown. (A) An
use RECIST 1.1, irRECIST, and iRECIST in their daily unenhanced, coronal, reformatted computed tomography (CT)
scan from a man aged 41 years with melanoma who received
clinical practice to follow their patients with cancer by immunotherapy reveals that numerous, small pulmonary nod-
repeated imaging studies and make decisions about contin- ules are present along the bronchovascular bundles and in the
subpleural regions, compatible with a perilymphatic pattern
ued therapy on the basis of both objective and symptomatic (arrows). (B) A contrast-enhanced, axial CT scan from a woman
criteria. However, these criteria may be limited and are not aged 37 years with lung cancer who received immunotherapy
demonstrates multiple, ill-defined pulmonary nodules in a peril-
always appropriate for routine clinical use in normal clinical ymphatic distribution (arrows) and thickening of bronchovascu-
therapy schemas, which frequently involve pauses of treat- lar bundles and interlobular septa in the left lung. In both of
these patients, the pulmonary findings resolved after discontin-
ment, modification of drug dosage, combined systemic and uation of therapy, and sarcoid-like reaction was diagnosed.
local tumor therapy, and treatment beyond progression, Sarcoid-like reaction is a rare complication that can manifest
which are not addressed by these criteria. with multiple micronodules with or without ground-glass opaci-
ties and/or mediastinal/hilar lymphadenopathy.

The Role of Positron Emission Tomography–2-

Deoxy-2-(Fluorine-18)Fluoro-D-Glucose/
Computed Tomography PET/CT) in the evaluation of patients who receive immuno-
The role of positron emission tomography–2-deoxy-2-(fluo- therapy is uncertain. One of the significant challenges with
rine-18)fluoro-D-glucose/computed tomography (FDG- FDG-PET/CT is the false-positive finding that can result

Cancer July 15, 2018 2915

Review Article

Figure 7. Imaging studies of thyroiditis are shown. (A,B) Contrast-enhanced, axial computed tomography (CT) scans from a
woman aged 49 years (A) before and (B) after the initiation of immunotherapy reveal a normal appearance of the thyroid gland
(A), which subsequently demonstrates enlargement (B). The patient’s thyroid function tests were abnormal, and a subsequent
ultrasound study confirmed a heterogenous and hypervascular thyroid, consistent with thyroiditis. (C) A fused, axial 2-deoxy-2-
(fluorine-18)fluoro-D-glucose (FDG)–positron emission tomography/CT image and (D) and a contrast-enhanced, axial CT scan
from a man aged 64 years with lung cancer who received immunotherapy demonstrate diffuse, increased FDG uptake through-
out the thyroid gland with mild enlargement and heterogeneous attenuation.

from increased FDG uptake by inflammatory processes,
which is an issue, because immunotherapy elicits a natural
inflammatory response, and immune-related adverse events
also may demonstrate increased FDG uptake. Two studies
in patients with melanoma demonstrated the inability of
FDG-PET/CT to differentiate between patients who had
pseudoprogression because of inflammatory infiltrate and
those who had actual PD.15,16 Cho et al evaluated the ability
of FDG-PET/CT in conjunction with other imaging
modalities to predict early response to therapy in patients
with advanced melanoma who receive treatment with several
checkpoint inhibitors.17 At each post-treatment time point,
response was assessed based on RECIST 1.1, irRC, Positron
Emission Tomography Response Criteria in Solid Tumors
(PERCIST 1.0), and European Organization for Research
and Treatment of Cancer criteria. Those authors developed
criteria comprised of anatomic and functional information
that predicted eventual response with 100% sensitivity, 93%
specificity, and 95% accuracy. FDG-PET/CT has demon-
strated benefit in evaluating the response of patients with
melanoma to treatment with BRAF and MEK inhibitors18
but has proven to be inadequate in examining responses to
immunotherapy for other cancers, such as renal cell
carcinoma.19

2916 Cancer July 15, 2018


Figure 8. Imaging studies of colitis are shown. (A) A
contrast-enhanced, coronal computed tomography (CT) scan
from a woman aged 61 years with lung cancer who received
immunotherapy demonstrates segmental wall thickening
involving the descending colon (arrow), consistent with coli-
tis. (B) A contrast-enhanced, axial CT scan from a man aged
23 years with melanoma who received immunotherapy
reveals diffuse thickening of the colon (arrows) and a small
amount of ascites (arrowheads). Segmental and diffuse colitis
have been described; the former has been associated with
watery or bloody diarrhea, and the latter resulted in watery
diarrhea.
Immune-Related Adverse Events
Over the course of therapy, unintended autoimmune-
mediated complications may develop because of altera-
tions in the host immune system. Complications related
to immunotherapy are referred to as immune-related
adverse events and may be the result of the induction of
either autoimmunity or a proinflammatory state.20 These
events tend to resolve with discontinuation of therapy,
Cancer July 15, 2018
Immunotherapy and the Role of Imaging/Carter et al
suggesting that they are not true autoimmune processes
but are the result of general immunologic enhancement.6
Analysis of clinical trial data has demonstrated significant
variability in the reporting quality of adverse events,21,22
which is typically inadequate.23-25 The most common
immune-related adverse event is dermatologic toxicity,
which may result in skin rash, and is typically low grade;
however, toxic necrotizing epidermolysis mucositis has
been reported.2,6 Additional effects include enterocolitis,
hepatitis, pneumonitis, and endocrinopathies, such as
hypophysitis, thyroiditis, and adrenal insufficiency. Other
complications of immunotherapy include sarcoid-like
reaction, acute kidney injury, pancreatitis, neurotoxicity,
cardiotoxicity, and ophthalmologic toxicity. Severe colitis
has the highest mortality and worst outcome associated
with immune-related adverse events.26
Imaging of Immune-Related Adverse Events
In evaluating patients who receive immunotherapy, it is
imperative for radiologists and other providers to recog-
nize unique adverse events to guide appropriate manage-
ment and prevent misinterpretation of studies. Side
effects often result in abnormalities that may be identified
on CT, MR imaging, or FDG-PET/CT performed for
restaging and/or surveillance. Immune-related adverse
effects may produce findings and metabolic changes
before the appearance of clinical symptoms, allowing early
change of therapy.1
Pneumonitis is the most common immune-related
adverse event in the chest. Chest radiography may be the
first imaging modality to demonstrate abnormalities
attributable to pneumonitis because of its widespread
availability and use; however, these findings are typically
incompletely characterized and nonspecific and are opti-
mally evaluated on chest CT. Naidoo and colleagues
demonstrated that only 67% of cases resulted in identifi-
able findings.27 In their study, several different patterns of
disease were identified, including: 1) a cryptogenic orga-
nizing pneumonia (COP)-like pattern (Fig. 3), 2)
ground-glass opacities (Fig. 4), 3) an interstitial pattern,
4) a hypersensitivity pneumonitis-like pattern, and 5)
pneumonitis not otherwise specified. The imaging find-
ings present in pneumonitis may evolve over time. For
instance, cases that are characterized by a COP-like pat-
tern may develop extensive ground-glass opacities. Others
with a predominantly ground-glass pattern may develop
interstitial abnormalities. A study of patients with
nivolumab-induced pneumonitis described 4 patterns on
chest CT: COP, nonspecific interstitial pneumonia,
hypersensitivity pneumonitis, and acute interstitial
2917
Review Article

Figure 9. Imaging studies of pancreatitis are shown. (A) A contrast-enhanced, axial computed tomography (CT) scan from a
man aged 57 years demonstrates focal, low attenuation in the body of the pancreas (arrow) and inflammatory changes in the
adjacent peripancreatic fat (arrowhead). (B) A fused, axial 2-deoxy-2-(fluorine-18)fluoro-D-glucose (FDG)–positron emission
tomography/CT study from a woman aged 48 years reveals focal, increased FDG uptake in the body of the pancreas that corre-
sponds to a region of focal parenchymal enlargement on the unenhanced CT image (arrows, C.).

pneumonia/acute respiratory distress syndrome.28 The
COP-like pattern manifests with patchy ground-glass
opacities and consolidation in a subpleural, peribronchial,
or band pattern, which may be observed with the reversed
halo sign. The nonspecific interstitial pneumonia pattern
includes bilateral ground-glass opacities with reticular
opacities, traction bronchiectasis or bronchiolectasis, and
minimal or absent honeycombing in a basal distribution
with subpleural sparing.29,30 The hypersensitivity pneu-
monitis pattern results in centrilobular nodules and
mosaic attenuation of the lung parenchyma because of air
trapping with an upper lobe-predominant distribution.30
Finally, the acute interstitial pneumonia/acute respiratory
distress syndrome pattern includes patchy, bilateral
ground-glass opacities with consolidation in the depen-
dent lung.30 Pneumonitis occasionally may result in the
appearance of nodular opacities in the lungs; however,
none of these findings should be misinterpreted as recur-
rent disease.
Sarcoid-like reaction is a rare immune-related
adverse event that can result in numerous small pulmo-
nary nodules in a perilymphatic distribution (along the
bronchovascular bundles and in the subpleural regions)
with or without ground-glass opacities and/or mediasti-
nal/hilar lymphadenopathy31 (Figs. 5 and 6). Involve-
ment of the airways is an uncommon complication of
immunotherapy that tends to affect the trachea. Cardio-
vascular abnormalities may be encountered, the most

2918 Cancer July 15, 2018


Figure 10. Imaging studies of cholangiopathy are shown. (A)
A contrast-enhanced, coronal, reformatted computed tomog-
raphy (CT) scan from a woman aged 76 years reveals mild
thickening and enhancement of the common bile duct wall
(arrow), with more extensive abnormality distally (arrow-
head). (B) A contrast-enhanced, coronal, reformatted CT
scan from a man aged 58 years reveals more extensive thick-
ening and enhancement of the common bile duct (arrow) as
well as some involvement of the left intrahepatic bile ducts
(arrowhead). Immune-related cholangiopathy may manifest
as thickening of the bile duct wall and/or biliary ductal
dilatation.
common of which is pericarditis, which can produce a
pericardial effusion and/or pericardial thickening on CT.
Imaging findings suggestive of ventricular interdepen-
dence and constrictive, effusive physiology (including
septal bounce and respiratory septal shift) may be present
Cancer July 15, 2018
Immunotherapy and the Role of Imaging/Carter et al
on echocardiography and MR imaging.32-34 The most
common complication involving the thyroid gland is
thyroiditis, which may be identified on iodine-123 thy-
roid scintigraphy and/or ultrasound. On CT, the thyroid
gland is typically enlarged and demonstrates heteroge-
neously low attenuation (Fig. 7). Immune-related thy-
roiditis may be identified on FDG-PET/CT as diffusely
increased FDG uptake (Fig. 7).
Several immune-related adverse events may affect
the abdomen and pelvis, the most common of which
include colitis and hepatitis. Colitis is a significant clinical
complication that has the highest mortality of all
immune-related adverse events, and prolonged time to
diagnosis and management is associated with poor out-
comes.35 On CT and MR imaging, immune-related coli-
tis may manifest as segmental or diffuse wall thickening,
mucosal enhancement, submucosal edema, air-fluid lev-
els, infiltration of the pericolonic fat, and ascites (Fig. 8).
Segmental and diffuse patterns of colitis were observed
with ipilimumab treatment: the former manifested clini-
cally with watery or bloody diarrhea, and the latter
resulted in watery diarrhea36. Other adverse events that
may affect the gastrointestinal tract include perforation
and bleeding. Immune-related pancreatitis results in
imaging findings similar to those from acute pancreatitis
unrelated to immunotherapy. On CT, enlargement and
an edematous appearance of the pancreas with adjacent
fat stranding, edema, and free fluid are most common37
(Fig. 9). Increased FDG uptake may be present on FDG-
PET/CT38 (Fig. 9). Autoimmune hepatitis may result in
periportal or portal vein hyperechogenicity on ultrasound
and periportal edema and hypoattenuation of the edema-
tous liver parenchyma on CT.39 Involvement of the bili-
ary system (cholangiopathy) may manifest as thickening
of the bile duct wall and/or biliary ductal dilatation (Fig.
10). Other abnormalities, including endocrinopathies like
hypophysitis (Fig. 11) and adrenal insufficiency, also may
be present. On MR imaging, hypophysitis manifests as
mild-to-moderate, diffuse pituitary enlargement without
compression of the optic chiasm. Thickening of the pitui-
tary gland is often present. After the administration of
intravenous gadolinium contrast material, homogeneous
and heterogenous pituitary enhancement may be
observed.40
FUTURE DIRECTIONS
Although irRC, irRECIST, and iRECIST represent con-
tinual improvement over the conventional WHO and
RECIST criteria for evaluating response to immunother-
apy, limitations and challenges remain, and further
2919
Review Article

Figure 11. Imaging studies of hypophysitis are shown. (A) An axial 2-deoxy-2-(fluorine-18)fluoro-D-glucose (FDG)–positron emis-
sion tomographic study from a man aged 65 years who had melanoma reveals focal increased FDG uptake in the region of the
pituitary gland (arrow). (B,C) Contrast-enhanced, coronal and sagittal, T1-weighted magnetic resonance images from the same
patient demonstrate enlarged and enhancing infundibulum (arrow in B) and pituitary gland (arrow in C).

refinements are warranted. In this effort, there is ongoing
work to develop volumetric imaging, dynamic contrast-
enhanced imaging, and molecular imaging for optimal
evaluation of immunotherapy response and immune-
related adverse events. Several novel PET radiotracers
involving amino acids, nucleotides, choline, and S recep-
tor to detect cell proliferation or cell death are currently
being investigated.41 In addition, investigational use of
MR imaging for depicting apoptosis and cell lysis to mon-
itor tumor response to immunotherapy also has been
reported.42 Other noninvasive imaging strategies are in
various stages of development and implementation.
Immuno-PET imaging is a noninvasive, quantitative
method of imaging the whole body using radiolabeled
monoclonal antibodies that can provide a means to evalu-
ate antibody drug pharmacokinetics and the expression of
cell surface markers of disease.43 Currently, immuno-
PET imaging is performed using copper-64 (64Cu)-
labeled and zirconium-89 (89Zr)-labeled antibodies.
Work has demonstrated that the detection of pro-
grammed death 1/programmed death ligand 1 (PD-1/
PD-L1) and/or CTLA4 with immuno-PET, as well as
single-photon emission CT (SPECT) radiolabeled with
indium-111 (In111), may improve patient identification,
stratification, and the early assessment of response.44
Recently, a preclinical study using granzyme B, a down-
stream effector of tumoral cytotoxic T cells, distinguished
treated responders from nonresponders with excellent
predictive ability.45 In addition, the group evaluated the
clinical value of a granzyme B imaging paradigm in which
they analyzed biopsy specimens from patients with mela-
noma who were receiving checkpoint inhibitor therapy.
In that study, there was a marked differential in granzyme
B expression between treated responders and nonrespond-
ers. The study suggests that granzyme B PET imaging can
serve as a quantitatively useful predictive biomarker for
efficacious responses to cancer immunotherapy. In
another preclinical study, 89Zr-desferrioxamine–labeled
anti-CD8 cys-diabody (89Zr-malDFO-169 cDb)
immuno-PET was developed for the tracking of endoge-
nous CD8-positive T cells, and the investigators observed
that the technique could detect changes in systemic CD8-
positive tumor-infiltrating lymphocytes in murine tumor
immunotherapy models.46 In a different study involving
64Cu-radiolabeled atezolizumab, specific binding to
tumor cells in vitro based on PET/CT imaging correlated
with PD-L1 expression levels.47 Other PET studies have
reported the feasibility of using peptide or small-molecule
compounds radiolabeled with gallium-68 or 111In to
assess PD-L1 expression.48,49
The term radiomics has been used to describe the
extraction of advanced quantitative imaging features
related to the underlying molecular features and pheno-
type of tumors from imaging modalities like CT, PET/
CT, and MR imaging. In contrast to the standard qualita-
tive imaging characteristics of neoplasms that are rou-
tinely evaluated on radiologic studies, advanced analytics
like texture analysis have the potential to uncover tumor
features that cannot be identified by visual assessment and
can provide detailed characterization of the specific tissue
or lesion of interest and the associated microenvironment.
A recent proof-of-concept study reported that radiomics
predicted pneumonitis in patients who received immuno-
therapy with an accuracy of 100%.50 Finally,

2920 Cancer July 15, 2018


radiogenomics, the linkage between imaging phenotypes
and tumor genomics, may assist in the development of
more robust stratification and endpoint imaging bio-
markers for molecular-targeted clinical trials.
CONCLUSIONS
The role of immunotherapy in treating patients with
cancer continues to expand. Therefore, it is essential that
radiologists and other providers have a thorough under-
standing of the novel response criteria developed to eval-
uate these patients, such as irRC, irRECIST, and
iRECIST. In addition, because a wide variety of
immune-related adverse events may affect patients who
receive immunotherapy, the prompt identification and
reporting of such side effects is imperative.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Brett W. Carter reports royalties from Elsevier, Inc. Wei T. Yang
reports personal fees from Seno Medical outside the submitted
work and royalties from Elsevier, Inc. Priya R. Bhosale made no
disclosures.
REFERENCES
1. Kwak JJ, Tirumani SH, Van den Abbeele AD, Koo PJ, Jacene HA.
Cancer immunotherapy: imaging assessment of novel treatment
response patterns and immune-related adverse events. Radiographics.
2015;35:424-437.
2. Nishino M, Tirumani SH, Ramaiya NH, Hodi FS. Cancer immu-
notherapy and immune-related response assessment: the role of radi-
ologists in the new arena of cancer treatment. Eur J Radiol. 2015;84:
1259-1268.
3. Okada H, Weller M, Huang R, et al. Immunotherapy response
assessment in neuro-oncology: a report of the RANO Working
Group. Lancet Oncol. 2015;16:e534-e542.
4. Wolchok JD, Hoos A, Bohnsack O, et al. Guidelines for the evalua-
tion of immune therapy activity in solid tumors: immune-related
response criteria. Clin Cancer Res. 2009;15:7412-7420.
5. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH,
Hodi FS. Developing a common language for tumor response to
immunotherapy: immune-related response criteria using unidimen-
sional measurements. Clin Cancer Res. 2013;19:3936-3943.
6. Postow MA, Wolchok JD. Ipilimumab: developmental history, clini-
cal considerations and future perspectives. Melanoma Lett. 2012;30:
1-4.
7. World Health Organization (WHO). WHO Handbook for Report-
ing Results of Cancer Treatment. Offset Publication No. 48.
Geneva, Switzerland: WHO; 1979.
8. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to
evaluate the response to treatment in solid tumors. J Natl Cancer
Inst. 2000;92:205-216.
9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evalua-
tion Criteria in Solid Tumours: revised RECIST guideline (version
1.1). Eur J Cancer. 2009;45:228-247.
10. Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimiz-
ing immune-related tumor response assessment: does reducing the
number of lesions impact response assessment in melanoma patients
treated with ipilimumab [serial online]? J Immunother Cancer. 2014;
2:17.
Cancer July 15, 2018
Immunotherapy and the Role of Imaging/Carter et al
11. Henze J, Maintz D, Persigehl T. RECIST 1.1, irRECIST 1.1, and
mRECIST: how to do [serial online]. Curr Radiol Rep. 2016;4:48.
12. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for
response criteria for use in trials testing immunotherapeutics. Lancet
Oncol. 2017;18:e143-e152.
13. Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related
response criteria: irRECIST. Ann Oncol. 2014;25(suppl 4):iv361-
iv372.
14. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related
response criteria and RECIST v1.1 in patients with advanced mela-
noma treated with pembrolizumab. J Clin Oncol. 2016;34:1510-
1517.
15. Bier G, Hoffmann V, Kloth C, et al. CT imaging of bone and bone
marrow infiltration in malignant melanoma—challenges and limita-
tions for clinical staging in comparison to 18FDG-PET/CT. Eur J
Radiol. 2016;85:732-738.
16. Kong BY, Menzies AM, Saunders CA, et al. Residual FDG-PET
metabolic activity in metastatic melanoma patients with prolonged
response to anti-PD-1 therapy. Pigment Cell Melanoma Res. 2016;29:
572-577.
17. Cho SY, Lipson EJ, Im HJ, et al. Prediction of response to immune
checkpoint inhibitor therapy using early-time-point F-FDG PET/CT
imaging in patients with advanced melanoma. J Nucl Med. 2017;58:
1421-1428.
18. Wong ANM, McArthur GA, Hofman MS, Hicks RJ. The advan-
tages and challenges of using FDG PET/CT for response assessment
in melanoma in the era of targeted agents and immunotherapy. Eur
J Nucl Med Mol Imaging. 2017;44(suppl 1):67-77.
19. Gilles R, de Geus-Oei LF, Mulders PFA, Oyen WJG. Immunother-
apy response evaluation with F-FDG-PET in patients with advanced
stage renal cell carcinoma. World J Urol. 2013;31:841-846.
20. Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immu-
notherapy of Cancer consensus statement on tumour immunother-
apy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol.
2013;10:588-598.
21. Ioannidis JP, Lau J. Completeness of safety reporting in randomized
trials: an evaluation of 7 medical areas. JAMA. 2001;285:437-443.
22. Pitrou I, Boutron I, Ahmad N, Ravaud P. Reporting of safety results
in published reports of randomized controlled trials. Arch Intern
Med. 2009;169:1756-1761.
23. Paoletti X, Le Tourneau C, Verweij J, et al. Defining dose-limiting
toxicity for phase 1 trials of molecularly targeted agents: results of a
DLT-TARGETT international survey. Eur J Cancer. 2014;50:2050-
2056.
24. Peron J, Maillet D, Gan HK, et al. Adherence to CONSORT
adverse event reporting guidelines in randomized clinical trials evalu-
ating systemic cancer therapy: a systematic review. J Clin Oncol.
2013;31:3957-3963.
25. Sivendran S, Latif A, McBride RB, et al. Adverse event reporting in
cancer clinical trial publications. J Clin Oncol. 2014;32:83-89.
26. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS; MDX010-20
Investigators. Patterns of onset and resolution of immune-related
adverse events of special interest with ipilimumab: detailed safety
analysis from a phase 3 trial in patients with advanced melanoma.
Cancer. 2013;119:1675-1682.
27. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated
with anti-programmed death-1/programmed death ligand 1 therapy.
J Clin Oncol. 2017;35:709-717.
28. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor-related
pneumonitis in advanced cancer patients: radiographic patterns and
clinical course. Clin Cancer Res. 2016;22:6051-6060.
29. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL,
Remy J. Fleischner Society: glossary of terms for thoracic imaging.
Radiology. 2008;246:697-722.
30. Travis WD, Costabel U, Hansell DM, et al. An official American Tho-
racic Society/European Respiratory Society statement: update of the
international multidisciplinary classification of the idiopathic intersti-
tial pneumonias. Am J Respir Crit Care Med. 2013;188:733-748.
31. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipili-
mumab: long-term follow-up of 177 patients with metastatic mela-
noma. Clin Cancer Res. 2012;18:2039-2047.
2921
Review Article
32. Yun S, Vincelette ND, Mansour I, Hariri D, Motamed S. Late onset
ipilimumab-induced pericarditis and pericardial effusion: a rare but
life threatening complication [serial online]. Case Rep Oncol Med
2015:794842, 2015.
33. Kolla BC, Patel MR. Recurrent pleural effusions and cardiac tampo-
nade as possible manifestations of pseudoprogression associated with
nivolumab therapy—a report of 2 cases [serial online]. J Immunother
Cancer. 2016;4:80.
34. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis
with combination immune checkpoint blockade. N Engl J Med.
2016;375:1749-1755.
35. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated
colitis: CT findings. AJR Am J Roentgenol. 2013;200:W468-W474.
36. O’Regan KN, Jagannathan JP, Ramaiya N, Hodi FS. Radiologic
aspects of immune-related tumor response criteria and patterns of
immune-related adverse events in patients undergoing ipilimumab
therapy. AJR Am J Roentgenol. 2011;197:W241-W246.
37. Bronstein Y, Ng CS, Hwu P, Hwu WJ. Radiologic manifestations of
immune-related adverse events in patients with metastatic melanoma
undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol.
2011;197:W992-W1000.
38. Alabed YZ, Aghayev A, Sakellis C, Van den Abbeele AD. Pancreati-
tis secondary to anti-programmed death receptor 1 immunotherapy
diagnosed by FDG PET/CT. Clin Nucl Med. 2015;40:e528-e529.
39. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated
hepatitis: imaging and clinicopathologic findings. Invest New Drugs.
2013;31:1071-1077.
40. Faje AT, Sullivan R, Lawrence D, et al. Ipilimumab-induced hypo-
physitis: a detailed longitudinal analysis in a large cohort of patients
with metastatic melanoma. J Clin Endocrinol Metab. 2014;99:4078-
4085.
2922
41. Aarntzen EH, Srinivas M, Radu GC, et al. In vivo imaging of
therapy-induced anti-cancer immune responses in humans. Cell Mol
Life Sci. 2013;70:2237-2257.
42. Lazovic J, Jensen MC, Ferkassian E, Aguilar B, Raubitschek A,
Jacobs RE. Imaging immune response in vivo: cytolytic action of
genetically altered T cells directed to glioblastoma multiforme. Clin
Cancer Res. 2008;14:3832-3839.
43. Wu AM, Senter PD. Arming antibodies: prospects and challenges
for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146.
44. Bauckneht M, Piva R, Sambuceti G, Grossi F, Morbelli S. Evalua-
tion of response to immune checkpoint inhibitors: is there a role for
positron emission tomography? World J Radiol. 2017;9:27-33.
45. Larimer BM, Wehrenberg-Klee E, Dubois F, et al. Granzyme B
PET imaging as a predictive biomarker of immunotherapy response.
Cancer Res. 2017;77:2318-2327.
46. Tavare R, Escuin-Ordinas H, Mok S, et al. An effective immuno-
PET imaging method to monitor CD8-dependent responses to
immunotherapy. Cancer Res. 2016;76:73-82.
47. Lesniak WG, Chatterjee S, Gabrielson M, et al. PD-L1 detection in
tumors using [Cu]atezolizumab with PET. Bioconj Chem. 2016;27:
2103-2110.
48. Mayer AT, Natarajan A, Gordon SR, et al. Practical immuno-PET
radiotracer design considerations for human immune checkpoint
imaging. J Nucl Med. 2017;58:538-546.
49. Chatterjee S, Lesniak WG, Miller ME, et al. Rapid PD-L1 detection
in tumors with PET using a highly specific peptide. Biochem Biophys
Res Commun. 2017;483:258-263.
50. Colen RR, Fujii T, Bilen MA, et al. Radiomics to predict
immunotherapy-induced pneumonitis: proof of concept [published
online ahead of print October 27, 2017]. Invest New Drugs. doi:
10.1007/s10637-017-0524-2.
Cancer July 15, 2018