Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

Abstract

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

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P O S I T I O N A R T I C L E A N D G U I D E L I N E S Open Access
Managing toxicities associated with
immune checkpoint inhibitors: consensus
recommendations from the Society for
Immunotherapy of Cancer (SITC) Toxicity
Management Working Group
I. Puzanov
1†
, A. Diab
2†
, K. Abdallah
3
, C. O. Bingham III
4
, C. Brogdon
5
, R. Dadu
2
, L. Hamad
1
, S. Kim
2
, M. E. Lacouture
6
,
N. R. LeBoeuf
7
, D. Lenihan
8
, C. Onofrei
9
, V. Shannon
2
, R. Sharma
1
, A. W. Silk
12
, D. Skondra
10
, M. E. Suarez-Almazor
2
,
Y. Wang
2
, K. Wiley
11
, H. L. Kaufman
12†
, M. S. Ernstoff
1*†
and on behalf of the Society for Immunotherapy of Cancer
Toxicity Management Working Group
Abstract
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based
therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a
discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic
mechanisms responsible for the drugs’therapeutic effects, namely blockade of inhibitory mechanisms that suppress
the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut,
endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal,
neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in
severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related
deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and
prolonged duration compared to adverse events from chemotherapy, and effective management depends on early
recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an
urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and
manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society
for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met
for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their
consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
Keywords: Immune-related adverse events, Toxicity, Immune checkpoint inhibitor
* Correspondence: Marc.Ernstoff@RoswellPark.org
†
Equal contributors
1
Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95
DOI 10.1186/s40425-017-0300-z

Background
Cancer immunotherapy has revolutionized the treatment
of cancer [1, 2]. Currently, the most widely used ap-
proach is the administration of targeted monoclonal
antibodies (mAbs) directed against regulatory immune
checkpoint molecules that inhibit T cell activation [1].
At present, six immune checkpoint inhibitors (ICIs) are
approved by the U.S Food and Drug Administration
(FDA) for use in a variety of solid tumors, and one
hematological malignancy (Hodgkin lymphoma) [3]. Ipi-
limumab, a fully human IgG1 mAb that blocks the cyto-
toxic T lymphocyte-antigen-4 (CTLA-4), a checkpoint
inhibitor of T cell activation, was the first ICI approved,
in 2011, for use in advanced melanoma [4]. Pembrolizu-
mab and nivolumab, both engineered IgG4 mAbs that
regulate T cell activation by blocking the protein pro-
grammed death 1 (PD-1), received FDA approval in pa-
tients with advanced melanoma in 2014 [5, 6] and the
indications for both have subsequently expanded consid-
erably. Indeed, in a landmark regulatory step, the FDA re-
cently approved both pembrolizumab and nivolumab for
use in certain patients with mismatch repair deficient
(dMMR) and microsatellite instability high (MSI-H)
cancers that have progressed following treatment with
chemotherapy –the first such ‘tissue-agnostic’,biomarker-
driven approvals granted [5, 6]. Both anti-PD-1 agents
are associated with negligible antibody-dependent cell-
mediated cytotoxicity (ADCC), a process that could be det-
rimental to the activation of T effector cells. After approval
of nivolumab for the treatment of non-small cell lung car-
cinoma (NSCLC) in 2015, the first immunotherapy com-
bination of ipilimumab plus nivolumab was granted
approval later in 2015, again in advanced melanoma [5].
More recently, the FDA approved three new ICIs, ate-
zolizumab, durvalumab and avelumab, all of which are
antibodies directed against the protein programmed
death-ligand 1 (PD-L1). Both atezolizumab and durvalu-
mab are engineered IgG1 mAbs that include Fc modifica-
tions that eliminate ADCC, while avelumab includes a
wildtype IgG1 framework with intact ADCC. Since May
2016, atezolizumab and durvalumab have both been ap-
proved for the treatment of NSCLC and urothelial carcin-
oma, and avelumab was approved for use in Merkel cell
carcinoma and urothelial carcinoma [7–9].
Immune-related adverse events (irAEs) are discrete
toxicities caused by non-specific activation of the im-
mune system, and can affect almost any organ system.
In some studies, the reported incidence is as high as 90%
for any-grade irAEs due to single-agent ICI therapy [10],
but meta-analysis indicates an overall incidence <75% with
anti-CTLA-4 monotherapy (ipilimumab) [11], and ≤30% in
phase 3 trials of anti-PD-1/PD-L1 agents [12–14]. IrAEs ≥
grade 3 severity occur in up to 43% of patients taking
ipilimumab [10] and ≤20% taking PD-1/PD-L1 agents
[12, 15]. The incidence of irAEs with ipilimumab and
pembrolizumab is dose-dependent, with greater toxicity at
higher dose levels; toxicity also varies between the adju-
vant and metastatic disease settings [10, 16–19]. There is
significant variance in definitions of toxicity severity across
disciplines, as well as variation in how symptoms and
signs that may be attributable to the same underlying
pathophysiology are reported. This causes considerable
difficulty in obtaining accurate data on incidence and
prevalence based on clinical trials [12]. Nonetheless, the
incidence of most irAEs with ICI monotherapy appears to
be broadly similar across tumor types [12]. Some of the
mechanisms that underpin the development of inflamma-
tory toxicity –in particular those driven by CD8 T cell
activity –overlap with those responsible for the drugs’
therapeutic effects. However, the exact pathogenesis of
immune toxicity is not clear, and many other inflamma-
tory cells, such as Th17 and other types of cells, are re-
ported to be involved. The mechanism of toxicity may
also vary by ICI, and may ultimately affect acuity, chron-
icity and management. In some cases, irAEs may occur in
patients with durable responses to treatment; this associ-
ation has not been fully ascertained [20, 21].
With increasing patient exposure to immunotherapy,
the nature and range of irAEs is becoming more clearly
defined, and several new but serious adverse events have
been reported [22]. Skin, gut, endocrine, lung and muscu-
loskeletal irAEs are relatively common, whereas, cardiovas-
cular, hematologic, renal, neurologic and ophthalmologic
irAEs are well-recognized but occur much less frequently
(Fig. 1). Although the majority of irAEs are mild to moder-
ate in severity, serious, occasionally life-threatening irAEs
(e.g., severe colitis, pneumonitis, encephalitis, toxic epider-
mal necrolysis, myocarditis, and autoimmune type I dia-
betes mellitus [T1DM] presenting as diabetic ketoacidosis),
are reported in the literature, and treatment-related deaths
have been reported in up to 2% of patients in clinical trials
[14, 23, 24]. As life-threatening irAEs are rare, and may
mimic other better-known conditions, there is growing
recognition of the need to educate both the oncology and
general medical communities in recognizing and institut-
ing urgent and appropriate treatment of these conditions.
Immune-related AEs resulting from immunotherapy can
have a delayed onset and prolonged duration compared to
adverse events resulting from chemotherapy (Fig. 2), in
part due to pharmacodynamic differences. Moreover, the
relationship between irAEs and dose/exposure remains to
be fully established [25]. As such, clinicians must remain
vigilant to the diverse clinical presentations of irAEs and
the possibility that patients maypresentwithirAEslatein
the course of treatment, and –in some cases –months or
even years after treatment discontinuation [26, 27].
Nonetheless, since diagnostic tests may be invasive and
potentially costly, investigations should be undertaken
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 2 of 28

judiciously and reserved for situations when the results
will guide patient management. Table 1 provides a list of
recommended tests to consider in all patients prior to ini-
tiating checkpoint inhibitor therapy.
Effective management of irAEs depends on early rec-
ognition and prompt intervention with immune suppres-
sion and/or immunomodulatory strategies appropriate
to the affected organ and the severity of toxicity. Special-
ist physicians, nurses and pharmacists familiar with
irAEs should be involved early, and hospitalization may
be necessary in serious (≥grade 4) or grade 3 irAEs that
do not respond to therapy, or to expedite work-up and
prevent complications from potentially life-threatening
irAEs [28]. Patient education on the potential for irAE
development is a key component of any pre-treatment
discussion with patients considered suitable candidates
for immunotherapy. It is also important to establish
physician networks to share outcomes of successful irAE
treatment strategies. Short-term adverse events due to
the use of moderate to high dose corticosteroids (e.g.,
opportunistic infections, sleep disturbance, gastritis, and
hypertension) should be anticipated. Patients receiving
long-term or high dose corticosteroids are at risk of de-
veloping diabetes mellitus and osteoporosis and should
receive vitamin D and calcium supplementation and, in
some cases, antibiotic prophylaxis [28]. However, con-
flicting reports on the associated between antibiotic use
and ICI efficacy pose as yet unanswered about whether
routine antimicrobial prophylaxis is appropriate in pa-
tients receiving ICIs [29, 30]. For steroid-refractory cases
and/or when steroid sparing is desirable, management
should be coordinated with disease specialists. Other im-
munomodulatory agents, such as infliximab, other
tumor necrosis factor inhibitors (TNFi), mycophenolate
mofetil, anti-thymocyte globulin (ATG), calcineurin in-
hibitors, methotrexate, or intravenous immunoglobulin
(IVIG) and plasmapharesis may be required. However,
besides TNFi for colitis, these immunosuppressive treat-
ments have not been evaluated in large numbers of pa-
tients. Some retrospective analyses suggest that use of
corticosteroids for the management of irAEs is not asso-
ciated with inferior results of therapy [31, 32] but, due
Fig. 1 Distribution of mild and severe immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. [Adapted from [88]]
Fig. 2 Pharmacokinetic/pharmacodynamic differences between chemotherapy and immunotherapy. Reproduced with permission from [25].
Dotted blue line represents waning of the biological effects of immunotherapy over time, and solid blue line represents early or late toxic effects.
Horizontal dotted blue arrow therefore represents duration of immunotherapy treatment benefit
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 3 of 28

to confounding, the association of irAEs with immuno-
logic activity from immunosuppression, and with individ-
ual patient efficacy, is not clear. The effects of alternative
forms of immunosuppression on the efficacy of ICIs have
not yet been sufficiently studied.
As physicians, nurses and patients become aware of the
value of immune-based treatments, including the syner-
gies offered by combination immunotherapy strategies,
there is a pressing need for guidance on how to recognize,
report and manage irAEs that arise in the course of treat-
ment. The Common Terminology Criteria for Adverse
Events (CTCAE) [33], a descriptive lexicon of terms and
adverse event severity, was developed by the National
Cancer Institute (NCI) at the National Institutes of Health
(NIH), with the goal of standardizing AE reporting across
medical specialties. However, increasing use of immuno-
therapy has clarified limitations in how immune-related
toxicities are addressed and classified within the current
CTCAE, as well as in other databases such as the Medical
Dictionary for Regulatory Activities (MedDRA). Import-
antly, the need for formal pathways for reporting
suspected irAEs has also highlighted the tendency for
CTCAE grading to under- or over-estimate true irAE inci-
dence and/or severity [28]. In certain settings, such as with
rheumatologic irAEs, CTCAE criteria are difficult to apply
and do not allow accurate recording of the severity and
impact of irAEs, especially as conditions may become
chronic [34]. These shortcomings present an opportunity
to improve and streamline irAE reporting in the next
versions of CTCAE and MedDRA. Similarly, since drug
labels for FDA-approved checkpoint inhibitors are based
on clinical trial data for individual drugs and do not
always align across therapeutic class, clinicians need
multidisciplinary, broad perspective guidance on how to
manage organ-specific toxicities.
To this end, the Society for Immunotherapy of Cancer
(SITC) established a Toxicity Management Working Group
to develop consensus recommendations on management
of irAEs that develop following ICI therapy until evidence-
based data are available to inform clinical decision-making.
This report represents the outcome of a recent workshop
to standardize toxicity management. The results represent
consensus thinking by a multidisciplinary group of experts
in the field but should not replace sound clinical judgment
or personalized drug management, as immunotherapy pa-
tients often require highly individualized management.
Methods
Consensus group representation
In response to the need for a collaborative, multidisciplin-
ary approach to the management of ICI toxicities, the SITC
convened a one-day workshop on March 31st, 2017, in
Washington D.C. The meeting was a multi-stakeholder ef-
fort with participation from approximately 85 experts from
academia, government, industry, scientific organizations
and other related entities. Representation was sought from
medical oncologists, surgeons, disease subspecialists, basic
scientists, pharmacists, industry clinical, regulatory and
safety experts and nurses. In order to streamline recom-
mendations across the range of organizations active in
the area of cancer immunotherapy, SITC invited rep-
resentatives from the American Society of Clinical
Table 1 Pre-treatment evaluation and diagnostic tests to
consider in all patients prior to initiating checkpoint inhibitor
therapy
Routine pre-treatment screening
History
♦Detailed questioning for autoimmune, infectious disease, endocrine
and organ-specific disease history
♦History of base line bowel habit (frequency of bowel movements,
usual stool consistency)
Blood tests
♦CBC
♦CMP
♦TSH
♦HbA1c
♦Free T4
♦Total CK
♦Infectious disease screen: HBsAg, HBsAb, HBcAb, hCAb, CMV
antibody, T-spot test, HIV antibody, HIV antigen (p24)
a
♦Fasting lipid profile
Dermatologic examination
♦Full skin and mucosal exam, taking note of the extent and type of
lesions present
Pulmonary tests
♦Baseline oxygen saturation on room air and during ambulation
Cardiac tests
♦ECG
♦Troponin I or T: baseline and weekly for 6 weeks
b
Additional screening tests recommended in patients with pre-existing
organ disease/at risk of organ-specific toxicity
Endocrine tests
♦8 am cortisol
♦8 am ACTH
Cardiac tests
♦Brain natriuretic peptide (BNP) or N-terminal pro B-type natriuretic
peptide (NT pro-BNP)
Pulmonary tests
♦PFTs
c
♦6MWT
c
In certain settings, some of these tests may not be readily available. Until their use
is firmly supported by evidence, individual physician judgment is recommended
a
These tests become very relevant if patients develop irAEs and require
immunosuppressive treatment such as steroids and/or anti-TNFαtreatment
b
Given the rarity of cardiac toxicity, this may not be cost-effective as a routine
test. . Baseline troponin should be measured although the follow up interval
for re-testing is not determined. Any suspicious cardiopulmonary symptoms
warrant repeat troponin and natriuretic testing in this population
c
Given the rarity of pulmonary toxicity, pre-treatment PFTs and 6MWTs should
considered in patients with pre-existing lung disease (chronic obstructive
pulmonary disease, interstitial lung disease, sarcoidosis, pulmonary fibrosis
etc.) and may not be feasible in all patients
ACTH, Adrenocorticotropic hormone; CBC, Complete blood count; CMP,
Complete metabolic panel; CMV, Cytomegalovirus; CK, Creatine kinase; ECG,
Electrocardiogram; HbA1c, Glycosylated hemoglobin; HBsAg, Hepatitis B surface
antigen; HBsAb, Hepatitis B surface antibody; HBcAb, Hepatitis B core antibody;
HCAb, Hepatitis C antibody; HIV, Human Immunodeficiency Virus; PFTs,
Pulmonary function tests; TSH, Thyroid-stimulating hormone; T4, Thyroxine;
6MWT, 6 min walk test
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 4 of 28

Oncology (ASCO), National Comprehensive Cancer Net-
work (NCCN), Parker Institute for Cancer Immunother-
apy, Friends of Cancer Research, American Association
for Cancer Research (AACR), Association of Community
Cancer Centers (ACCC), NCI and the Oncology Nursing
Society (ONS) to participate in the workshop. To ensure
that commercial interests did not influence the outcomes
of the workshop, industry representatives participated in
group discussions but final approval of the workshop out-
put, and of this manuscript, was the responsibility of the
organizing committee, none of whom are employed by a
pharmaceutical or biotechnology company. Representa-
tives from the Office of Hematology and Oncology Prod-
ucts, Center for Drug Evaluation and Research (CDER),
were invited to review and provide feedback on the
final manuscript. Individuals selected as authors were
workshop organizers and lead discussants for individual
organ-specific toxicity breakout groups. All participants
were required to disclose any potential conflicts of interest
prior to participation.
Workshop objectives and procedures
The overarching goals of the workshop were twofold: 1)
to develop treatment algorithms for managing common
and rare immunotherapy-related toxicities and 2) to de-
velop standardized templates, including inclusion and
exclusion criteria, for irAE management in clinical trial
protocols (which will be reported separately). More
broadly, participants were charged with describing the
spectrum of immune-related toxicities and providing
recommendations on recognizing, monitoring and man-
aging these toxicities. To facilitate discussion among ex-
perts in different medical fields, attendees broke out into
11 subgroups (‘breakout groups’) that focused on irAEs
identified by body system (dermatologic, gastrointestinal,
endocrine, pulmonary, rheumatologic, cardiovascular,
hematologic, renal, neurologic and ophthalmologic) as
well as infusion reactions. These breakout groups were
generally supplemented with disease subspecialty expert-
ise focused on the area of interest. Each breakout group
received instructions to guide their discussion, a list of
recognized toxicities by system, relevant drug package
inserts, several key supporting references, and a copy of
CTCAE version 4.0. A working draft of the Friends of
Cancer Research/Parker Institute for Cancer Immuno-
therapy guidelines on monitoring, management and
follow-up of irAEs from anti-PD-1/PD-L1 agents was
also distributed [35].
After separate breakout group discussions, one repre-
sentative from each group presented their recommenda-
tions to all participants, and responded to questions and
additional suggestions from the wider group. Following
the meeting, recommendations made on-site were recir-
culated by email to participants from each breakout
group to ensure all views and opinions were captured.
The final recommendations on management of irAEs
presented in this paper therefore represent the views of
each multidisciplinary expert group. These recommen-
dations are not intended to provide comprehensive med-
ical guidance on the management of disorders that may
arise from use of immunotherapy treatment; specialist
care should be sought as necessary, and as indicated in
treatment-specific guidelines.
Strengths and limitations of the consensus
recommendations
These consensus recommendations represent the views
of a broad range of experts from multiple fields of
expertise, and from large cancer organizations with differ-
ing areas of focus. In some cases they are driven by evi-
dence from the published literature; in others, particularly
where data are lacking, they are guided by accumulated
clinical experience and practice. The participation of
stakeholders from the pharmaceutical and biotechnology
industries is another strength, ensuring that those in-
volved in drug research and development are part of the
discussion and that there is access to large industry-
collected patient databases. However, it is important to ac-
knowledge that evidence gaps are considerable, consensus
was not reached on all issues, and many questions remain
unanswered. Furthermore, not all working groups had
representation from all specialist groups (oncologist, dis-
ease specialist, nurse, pharmacist). The recommendations
may not take into account reimbursement restrictions that
could limit access to recommended drugs for some pa-
tients. Lastly, but importantly, there was no patient repre-
sentation. Finally, the recommendations addressed in this
document reflect irAEs related to PD-1/PD-L1 and
CTLA-4 inhibitors, and do not address toxicity that may
ensue following administration of other classes of im-
munotherapy, including chimeric antigen receptor T cell
(CAR T) therapy. It is unclear to what extent the recom-
mendations can be generalized to immunotherapy agents
other than those addressed in this manuscript, including
agents in development.
Consensus recommendations
The recommendations for managing toxicities associated
with ICIs, below, represent the consensus views of par-
ticipants in the 11 body system groups. Overall, irAEs
are broken down into two major categories, based on
the opinions of the workshop organizers regarding the
frequency with which they are seen in clinical practice:
frequently reported (dermatologic, gastroenterological,
endocrine, respiratory, and rheumatologic/musculoskel-
etal) and uncommon (cardiovascular, hematologic, renal,
neurologic and ophthalmologic). Infusion reactions, which
are more common with mAbs based on a wildtype IgG1
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 5 of 28

backbone and less common with IgG4 antibodies, are also
addressed. Within each body system, information is di-
vided into three sections: clinical presentation and epi-
demiology, diagnostic evaluation, and guidance on when
to refer to a disease specialist.
Management of irAEs relies heavily on corticosteroids,
and other immunomodulatory agents, which should be
prescribed judiciously to reduce the potential for short
and long-term complications. It remains unclear whether
prophylactic antibiotics should routinely be prescribed to
reduce the potential for opportunistic infection in patients
receiving steroids. Broadly, corticosteroid management
can be approached as shown in Table 2, but treatment
should be individualized depending on each patient’smed-
ical history; co-morbidities; underlying disease status; type,
number and severity of adverse events; ICI administered;
and ability to tolerate corticosteroids.
Table 3 summarizes the recommended management of
recognized irAEs across body systems.
Frequently reported immune-related adverse events
Dermatologic adverse events
Clinical presentation and epidemiology Maculopapu-
lar rash and pruritus are common reactions to ICIs but
lichenoid, eczematous, and bullous dermatitis, and psoria-
sis have also been reported, albeit less frequently. Vitiligo
is frequently seen in the melanoma patient population.
Dermatologic toxicity (all grades) is reported in 30–40%
of patients taking PD-1/PD-L1 inhibitors [13, 15], and
approximately 50% of patients treated with ipilimu-
mab [13]. A systematic review of the literature reported
that 13–20% of patients taking pembrolizumab or nivolu-
mab developed rash or pruritus (all-grade) and approxi-
mately 8% (all with melanoma) developed vitiligo [36],
which is associated with tumor response [20]. More re-
cently, several cases of hair re-pigmentation have also been
described in patients treated with anti-PD1 or anti-PD-L1
therapy [37]. Onset of skin irAEs typically occurs within
days or weeks of treatment [38] although onset may be de-
layed, appearing after several months of treatment [39].
Most dermatologic irAEs are low-grade and manageable,
[13, 36] although rare, potentially life-threatening exfolia-
tive dermatological conditions such as Stevens-Johnson
Syndrome/toxic epidermal necrolysis (SJS/TEN), and drug
rash with eosinophilia and systemic symptoms (DRESS)
have been reported [28]. Severe irAEs tend to occur more
commonly with combination ICI therapy [40]. Any clinical
suspicion of such reactions should prompt immediate spe-
cialist referral. Permanent discontinuation of immunother-
apy is mandatory for grade 4 dermatologic irAEs, SJS/
TEN, or DRESS syndrome.
Diagnostic evaluation: Given the frequency and persist-
ence of skin toxicities with ICIs, dermatologic assess-
ments are warranted in patients with a known history of
immune-related skin disorders such as psoriasis, bullous
pemphigoid or lupus. Non-specific maculopapular erup-
tions are commonly reported, which may, in part, reflect
the limitations of CTCAE in the classification of specific
subsets of skin disorders. Whenever possible, the irAE
should be categorized since management algorithms re-
flect the approach to idiopathic skin disorders, beyond
systemic immune suppression with steroids. Patients
Table 2 General guidance for corticosteroid management of immune-related adverse events
Grade of immune-related AE
(CTCAE/equivalent)
Corticosteroid management Additional notes
1•Corticosteroids not usually indicated •Continue immunotherapy
2•If indicated, start oral prednisone 0.5-1 mg/kg/day if patient
can take oral medication.
•If IV required, start methylprednisolone 0.5-1 mg/kg/day IV
•If no improvement in 2–3 days, increase corticosteroid dose to
2 mg/kg/day
•Once improved to ≤grade 1 AE, start 4–6 week steroid taper
•Hold immunotherapy during corticosteroid use
•Continue immunotherapy once resolved to ≤grade
1 and off corticosteroids
•Start proton pump inhibitor for GI prophylaxis
3•Start prednisone 1-2 mg/kg/day (or equivalent dose of
methylprednisolone)
•If no improvement in 2–3 days, add additional/alternative
immune suppressant
•Once improved to ≤grade 1, start 4–6-week steroid taper
•Provide supportive treatment as needed
•Hold immunotherapy; if symptoms do not improve
in 4–6 weeks, discontinue immunotherapy
•Consider intravenous corticosteroids
•Start proton pump inhibitor for GI prophylaxis
•Add PCP prophylaxis if more than 3 weeks of
immunosuppression expected (>30 mg prednisone
or equivalent/day)
4•Start prednisone 1-2 mg/kg/day (or equivalent dose of
methylprednisolone)
•If no improvement in 2–3 days, add additional/alternative
immune suppressant, e.g., infliximab
•Provide supportive care as needed
•Discontinue immunotherapy
•Continue intravenous corticosteroids
•Start proton pump inhibitor for GI prophylaxis
•Add PCP prophylaxis if more than 3 weeks of
immunosuppression expected (>30 mg prednisone
or equivalent/day)
Note: For steroid-refractory cases and/or when steroid sparing is desirable, management should be coordinated with disease specialists. AE, adverse event
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 6 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
DERMATOLOGIC Specialist referral?
Maculopapular rash/dermatitis
Grade Description Management
1 Macules/papules covering <10% BSA with
or without symptoms (e.g., pruritus, burning,
tightness)
•Continue ICI
•Oral antihistamines
○Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
•Topical corticosteroids
○Class I topical corticosteroid (clobetasol propionate,
halobetasol propionate, betamethasone dipropionate cream
or ointment) for body; Class V/VI corticosteroid (aclometasone,
desonide, hydrocortisone 2.5% cream) for face
2 Macules/papules covering 10–30% BSA with
or without symptoms (e.g., pruritus, burning,
tightness); limiting instrumental ADL
•Continue ICI
•Non-urgent dermatology referral
•Oral antihistamines
○Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
•Topical corticosteroids (see grade 1)
○As above
○Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
✓
3 Macules/papules covering >30% BSA with
or without associated symptoms; limiting
self-care ADL
•Hold ICI
•Same day dermatology consult
•Rule out systemic hypersensitivity: CBC with differential, CMP
•Oral antihistamines
○Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
•Systemic corticosteroids
•Prednisone 0.5 –1 mg/kg/day (or equivalent dose of
methylprednisolone) until rash resolves to ≤grade 1
✓
Pruritus*
Grade Description Management
1 Mild or localized; topical intervention
indicated
•Emollients with cream or ointment based, fragrance-free
products
○Class I topical corticosteroid (clobetasol propionate,
halobetasol propionate, betamethasone dipropionate) for
body; Class V/VI corticosteroid (aclometasone, desonide,
hydrocortisone 2.5%) for face, AND oral antihistamines
(e.g., cetirizine/loratidine 10 mg daily, hydroxyzine 10-
25 mg QID, or at bedtime
2 Intense or widespread; intermittent; skin
changes from scratching (e.g., edema, papulation,
excoriation, lichenification, oozing/crusts); oral
intervention indicated; limiting instrumental ADL
•Dermatology referral
•Class I topical steroid (clobetasol propionate, halobetasol
propionate, betamethasone dipropionate) for body; class V/VI
steroid (aclometasone, desonide, hydrocortisone 2.5%) for face,
AND oral antihistamines (e.g., cetirizine/loratidine 10 mg daily,
hydroxyzine 10-25 mg QID, or at bedtime
•Oral corticosteroids
○Prednisone 0.5 –1 mg/kg/day (or equivalent of
methylprednisolone) tapered over 2 weeks
✓
3 Intense or widespread; constant; limiting
self-care ADL or sleep; oral corticosteroid
or immunosuppressive therapy indicated
•Dermatology referral
•GABA agonist (pregabalin, gabapentin 100-300 mg TID)
•Oral corticosteroid
○Prednisone 0.5 –1 mg/kg/day (or equivalent of
methylprednisolone) tapered over 2 weeks
✓
Notes:
1. Grade 4 maculopapular rash/dermatitis is not included in CTCAE
*Recommendations provided are based on case reports, series and expert consensus. Use of suggested therapies must be discussed with medical
oncology based on individual patient considerations. The impact of these therapies on the anti-tumor immune response and efficacy of cancer
treatment is unknown and requires further research.
GASTROENTEROLOGICAL Specialist referral?
Colitis
Grade CTCAE description Management
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 7 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
[Grade 1 diarrhea frequency ≤4/day]
•Close follow up within 24–48 h for changes or progression
•Continue ICI
•If symptoms persist, start routine stool and blood tests
•Bland diet advisable during period of acute diarrhea
•Anti-diarrheal medication is optional but not highly
recommended when infectious work-up is negative.
2 Abdominal pain; mucus or blood in stool
[Grade 2 diarrhea frequency 4–6/day]
•Hold ICI
•Outpatient stool and blood work; CRP, ESR, fecal calprotectin,
lactoferrin, imaging and endoscopy are optional
•If diarrhea only, observe for 2–3 days. If no improvement start
prednisone 1 mg/kg/day (or equivalent dose of
methylprednisolone); anti-diarrheal medication is not
recommended
•If diarrhea and colitis symptoms (abdominal pain +/−blood in
BM), start prednisone 1 mg/kg/day (or equivalent dose of
methylprednisolone)immediately
○If no improvement in 48 h, increase corticosteroid dose
to prednisone 2 mg/kg/day (or equivalent dose of
methylprednisolone)
○If patient improves
▪Taper corticosteroid over 4–6 weeks may be needed
▪Resume ICI when corticosteroid is tapered to ≤10 mg/
day and patient remains symptom-free (grade ≤1)*
▪Continue anti-PD-1 or anti-PD-L1 monotherapy
▪If using combination anti-CTLA-4/anti-PD-1
immunotherapy, continue anti-PD-1 agent only
▪ICI dose reduction is not recommended
•If colitis returns on resuming ICI:
○Grade ≤2: temporarily hold ICI
○Grade ≥3: permanently discontinue ICI
✓
See note 5
3 and
4
Grade 3: Severe abdominal pain; change in
bowel habits; medical intervention indicated;
peritoneal signs
[Grade 3 diarrhea frequency ≥7×/day]
Grade 4: Life-threatening consequences;
urgent intervention indicated
•Grade 3: withhold ICI; consider resuming ICI when
corticosteroid is tapered to ≤10 mg/day and patient remains
symptom-free (grade ≤1). Consider hospitalization
•Grade 4: permanently discontinue ICI and hospitalize
•Blood and stool infection work-up, inflammatory markers,
imaging, endoscopy and GI consult
•Start intravenous prednisone 1-2 mg/kg/day (or equivalent
dose of methylprednisolone) immediately
○If patient improves, follow instructions for ‘If patient
improves’for grade 2
•If refractory or no improvement on IV corticosteroid, start
prednisone 2 mg/kg/day (or equivalent dose of
methylprednisolone) for 3 days
•Consider other anti-inflammatory agents e.g. infliximab 5 mg/
kg, which can be given again after two weeks if a second dose
is needed. Vedolizumab may also be used (see Note 4 below).
Notes:
1. CBC with differential, CMP, ESR and CRP are recommended before starting immunotherapy, to provide baseline values for comparison over time.
Despite the association between elevated ESR and CRP and colitis, some insurance companies may not cover these tests.
2. There is no proven role for prophylactic corticosteroids (budesonide) to prevent GI irAEs [45,47].
3. Response to infliximab generally occurs within 1–3 days although some patients benefit from a second dose after 2 weeks. Prolonged oral
prednisone taper may be required after infliximab administration. Whether infliximab reduces the antitumor efficacy of ipilimumab remains
unknown [103].
4. Case reports of successful treatment of steroid-dependent immune-related colitis using vedolizumab indicate this may benefit certain patients.
5. A GI consult is warranted in any patient who meets criteria for grade 2 diarrhea/colitis with negative infectious stool work up.
Hepatitis
Grade CTCAE Description (Note 1) Management
1 AST, ALT > ULN -3xULN; total bilirubin >
ULN-1.5xULN
•Continue ICI
•CMP or hepatic function panel once weekly
•If liver enzyme and function tests are stable, reduce frequency
of blood tests
2 AST, ALT >3- ≤5xULN; total bilirubin >
1.5 - ≤3xULN
•Hold ICI
•Rule out viral hepatitis, autoimmune disease, biliary obstruction,
new metastasis or thrombosis
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 8 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•Start prednisone 0.5-1 mg/kg/day (or equivalent dose of
methylprednisolone) with 4 week taper
•Monitor CMP twice a week
•Liver biopsy is optional
•Resume ICI when corticosteroid taper to 10 mg/day (toxicity
grade ≤1)
3 and
4
AST, ALT >5xULN; total bilirubin >3xULN •Permanently discontinue ICI
•Monitor CMP every 1–2 days
•Start prednisone 1–2 mg/kg/day
○If refractory after 3 days, consider mycophenolate
•If liver enzymes improve, taper corticosteroid over 4 weeks
•Consider liver biopsy
Notes:
1. Liver enzyme levels stated here are not defined in CTCAE and are instead drawn from reference [104]
2. In patients with liver metastasis, ICI can be used at baseline liver profile equivalent to grade 2. If ≥50% elevation in AST/
ALT lasting for ≥1 week, permanently stop ICI.
ENDOCRINE Specialist referral?
Hypophysitis
Grade CTCAE Description* Management
1 Asymptomatic or mild symptoms; clinical
or diagnostic observations only; intervention
not indicated
•Hold ICI if ≥grade 2 irAE until work up is completed and
appropriate hormone replacement is started
•If central adrenal insufficiency: start physiologic steroid replacement:
Hydrocortisone ~10 mg/m
2
(HC15mgam,5mgat3pm)
○Periodic assessment (e.g., every 3 months in the first year,
every 6 months thereafter): clinical monitoring and
repeat hormone levels (am cortisol and ACTH and/or low
dose cosyntropin stimulation test) to assess recovery
•If central hypothyroidism: start thyroid hormone (levothyroxine
1mcg/kg)
○Repeat thyroid function testing 6–8 weeks after initiation
of thyroid hormone and then periodically (e.g., every
3 months in the first year and every 6 months thereafter)
to assess recovery
•If central hypogonadism, repeat hormone levels in 2–3 months
and consider testosterone in men or HRT in women if
appropriate for cancer type
For severe/life-threatening symptoms such as adrenal crisis, severe
headache, visual field deficiency:
•Hospitalize as appropriate.
•High dose corticosteroid (prednisone 1 mg/kg/day) (or
equivalent dose of methylprednisolone) in the acute phase,
followed by taper over 1 month.
•Adrenal crisis should be managed per standard guidelines.
•If central hypothyroidism, replace thyroid hormone (see above)
after corticosteroids have been initiated
✓
2 Moderate; minimal, local or noninvasive
intervention indicated; limiting age-
appropriate instrumental ADL
3 Severe or medically significant but not
immediately life-threatening; hospitalization
or prolongation of existing hospitalization
indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent
intervention indicated
Note: In the uncommon scenario of MRI findings without pituitary deficiency, consider high dose corticosteroids for prevention of hormonal
dysfunction.
* Hypophysitis is not defined in CTCAE Version 4.0. This classification is drawn from the CTCAE category ‘Endocrine disorders –Other’.
Hypothyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
•Hold ICI for ≥grade 3 irAEs
•ICI can be continued after resolution of symptoms to grade 2
or better.
•Start standard thyroid replacement therapy: initial dose can be
the full dose (1.6 mcg/kg) in young, healthy patients, but a
reduced dose of 25 -50mcg should be initiated in elderly
patients with known cardiovascular disease.
•Repeat TSH and free T4 testing after 6–8 weeks and adjust
thyroid hormone dose accordingly. If TSH is above reference
range, increase thyroid hormone dose by 12.5 mcg to 25 mcg
•After identification of the appropriate maintenance dose,
further evaluation is required every year, or sooner if patient’s
status changes
✓
2 Symptomatic; thyroid replacement
indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL;
hospitalization indicated
4 Life-threatening consequences; urgent
intervention indicated
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 9 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•After identification of the appropriate maintenance dose,
further evaluation is required every year, or sooner if patient’s
status changes
Hyperthyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
•Hold ICI for ≥grade 3 irAEs
•Standard therapy for hyperthyroidism should be followed
•Thyroiditis is self-limiting and has 2 phases:
○In the hyperthyroid phase,patients may benefit from
beta blockers if symptomatic (e.g., atenolol 25–50 mg
daily, titrate for HR < 90 if BP allows). Monitor closely with
regular symptom evaluation and free T4 testing every
2 weeks.
○Introduce thyroid hormones (see hypothyroidism
management) if the patient becomes hypothyroid (low
free T4/T3, even if TSH is not elevated).
•Graves’disease should be treated per standard guidelines.
✓
2 Symptomatic; thyroid suppression therapy
indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL;
hospitalization indicated
4 Life-threatening consequences; urgent
intervention indicated
Note: High dose corticosteroids (1 mg/kg/day) are not routinely required.
Type 1 diabetes (CTCAE defines hyperglycemia not diabetes)
Grade CTCAE Description Management
1 Fasting glucose > ULN - 160 mg/dL
(>ULN - 8.9 mmol/L)
•Type 1 DM with diabetic ketoacidosis: Hold ICI; hospitalize and
initiate treatment per standard guidelines.
•Type 1 DM without diabetic ketoacidosis: Hold ICI for
hyperglycemia ≥grade 3. Treat with insulin and continue ICI
when patient recovers to grade 1.
•Treat with insulin per standard guidelines and restart ICI when
patient recovers to grade 1.
•Provide patient education on diet and lifestyle modification,
and blood glucose testing
✓
2 Fasting glucose >160–250 mg/dL
(>8.9–13.9 mmol/L)
3 Fasting glucose >250–500 mg/dL
(>13.9–27.8 mmol/L); hospitalization
indicated
4 Fasting glucose >500 mg/dL
(>27.8 mmol/L); life-threatening
consequences
PULMONARY Specialist referral?
Pneumonitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
•Consider holding ICI
•Consider pulmonary and infectious disease consultations
•Reimage at least prior to every cycle of ICI treatment (at least
every 3 weeks)
○If repeat imaging shows resolution of radiographic
findings, no further CT imaging is necessary; resume
therapy with close follow-up
○If evidence of progression, treat at higher grade
○If no change, consider continued therapy with close
follow-up for new symptoms
•If symptoms develop, treat at higher grade
•Self-monitor symptoms and oxygen saturation (using personal
pulse oximeter) every 2–3 days; weekly clinic visits
•If chest imaging abnormalities resolve, consider resuming
treatment with close follow-up
✓
2 Symptomatic; limiting instrumental ADL;
medical intervention indicated
•Hold ICI
•Consider hospitalization
•Pulmonary consultation for bronchoscopy with
bronchoalveolar lavage. Consider biopsies for atypical lesions
•Initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent)
○Day 2–3 of corticosteroids/supportive care: If symptoms
improve to ≤grade 2, start slow steroid taper over >1 month.
If symptoms do not improve, or worsen, treat as grade 3–4
•Consider drug re-challenge if symptoms and imaging
abnormalities resolve
✓
(pulmonary and
infectious disease)
3 Severe symptoms; limiting self-care ADL;
oxygen indicated
•Permanently discontinue ICI
•Hospitalize; consider ICU care
✓
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 10 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•Pulmonary consultation for bronchoscopy with
bronchoalveolar lavage. Consider biopsies for atypical lesions
•Initiate methylprednisolone IV, 2 mg/kg/day
•Day 2–3 of corticosteroids/supportive care:
○If no clinical improvement, add infliximab or
cyclophosphamide, mycophenolate mofetil or IVIG
○If clinical improvement: reduce corticosteroids to 1 mg/
kg/day and slowly taper over >2 months.
•Drug re-challenge:
○Grade 3: Consider drug re-challenge on a case-by-case
basis after discussions weighing risk/benefit with the
patient and only if symptoms and imaging abnormalities
resolve
○Grade 4: Permanent y discontinue ICI
(pulmonary and
infectious disease)
4 Life-threatening respiratory compromise;
urgent intervention indicated (e.g., intubation)
Notes:
1. Consider prophylactic antibiotics for pneumocystis pneumonia (PCP) for patients receiving at least 20 mg methylprednisolone or equivalent for
≥4 weeks
2. Consider calcium and vitamin D supplementation with prolonged steroid use
3. All patients with grade 2–4 pneumonitis receiving steroids should also be on proton pump inhibitor therapy for GI prophylaxis
4. T-spot testing should be undertaken to exclude tuberculosis in any patient being considered for anti-TNF therapy, prior to starting anti-TNF
treatment.
Sarcoidosis
Grade CTCAE Description Management
1 Not defined in CTCAE •Consider holding ICI
•Close follow-up
•Consider corticosteroids
•Hold ICI
•Consider corticosteroid therapy for patients with sarcoidosis
grade 2 or higher and any of the following:
○progressive radiographic change
○persistent and/or troublesome pulmonary symptoms
○lung function deterioration: TLC decline of ≥10%, FVC
decline of ≥15%; DLCO decline of ≥20%
○concomitant involvement of critical extrapulmonary
organ systems
○sarcoid-related hypercalcemia
•Corticosteroid dose: prednisone 1 mg/kg (or IV equivalent of
methylprednisolone) for grade 2 sarcoidosis or severe cases
requiring hospitalization. Taper steroids over 2–4 months,
depending on response
✓
✓
≥2
Notes: To date, there are no studies focusing on management of sarcoidosis as a side effect of checkpoint inhibitor therapy. Current
recommendations are based on clinical experience and case report publications.
RHEUMATOLOGIC/MUSCULOSKELETAL [78] Specialist referral?
Inflammatory arthritis
Grade CTCAE Description (Note 1) Management
1 Mild pain with inflammatory symptoms
(Note 2), erythema, or joint swelling (Note 3)
•Continue ICI
•Analgesics: NSAIDs: naproxen 500 mg BID or meloxicam 7.5–
15 mg daily orally for 4–6 weeks
•If NSAIDs ineffective, consider prednisone 10–20 mg daily for
2–4 weeks
•Consider intra-articular corticosteroid injection only if ≤2 joints
affected and low dose prednisone (10 mg/day) and NSAIDs
not effective
•If no improvement in 2–4 weeks, escalate to grade 2
management
•Conduct serial rheumatologic examinations (2 weeks, 4 weeks,
then 4–6 weekly) and functional assessment at follow-up
2 Moderate pain associated with signs
of inflammation, erythema, or joint
swelling; limiting instrumental ADL
•Consider holding ICI
•Rheumatology referral to confirm inflammatory arthritis, assess
need for intra-articular injection and examine for signs of early
bone damage
✓
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Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•Prednisone 20 mg daily for 2–4 weeks, increase to 1 mg/kg/
day, or equivalent. If no response in 2–4 weeks. Escalate to
grade 3 management
•If symptoms improve, taper corticosteroid over 4–8 weeks or
until grade 1
3 Severe pain associated with signs of
inflammation, erythema, or joint
swelling; irreversible joint damage (e.g.,
erosion); disabling; limiting self-care ADL
•Hold ICI
•Rheumatology referral
•Prednisone 1 mg/kg/day or equivalent for 2–4 weeks, or until
symptoms improve to grade 1
•Consider additional immunosuppression (Note 4) (e.g.
methotrexate [Note 5], sulfasalazine, leflunomide). Consider
anti-cytokine therapy (e.g. TNF-inhibition) [Note 6]
•If symptoms improve, taper corticosteroid over 4–8 weeks/until
grade 1; if symptoms do not improve in 4–6 weeks:
permanently discontinue ICI
✓
Notes:
1. CTCAE includes separate listings for arthritis, joint effusion and arthralgia although there is overlap in presenting symptoms such as pain and
effects on ADL
2. Joint stiffness after sleep or inactivity, improvement of symptoms with movement or heat.
3. Joint swelling refers to the clinical finding on examination, and may encompass soft tissue swelling, joint effusion or synovitis.
4. Before initiation of these drugs, screening for hepatitis B and C should be performed
5. Methotrexate should be administered at a starting dose of 15 mg weekly, with daily folic acid supplementation. Titrate up to a maximum of
25 mg weekly, or switch to injectable methotrexate if patient cannot tolerate orally
6. Before anti-cytokine therapy, evaluation for latent/active TB should be performed
INFUSION REACTIONS Specialist referral?
Grade CTCAE Description Management
1 Mild transient reaction; infusion interruption
not indicated; intervention not indicated
•Drug infusion rate may be decreased, or infusion temporarily
interrupted, until resolution of the event
•Consider reducing the rate of infusion upon re-initiation or
subsequent infusions
•Non-steroidal anti-inflammatory drugs (NSAIDs, e.g. acetamino-
phen), antihistamines, opioids, and corticosteroids may be used
per investigator/ institutional guidelines
•Consider premedication for subsequent infusions per
investigator/ institutional guidelines
2 Therapy or infusion interruption indicated
but responds promptly to symptomatic
treatment (e.g., antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic medications
indicated for ≤24 h.
3 Prolonged (e.g., not rapidly responsive to
symptomatic medication and/or brief
interruption of infusion); recurrence of
symptoms following initial improvement;
hospitalization indicated for clinical sequelae
•Permanently discontinue ICI
•For severe/life-threatening reactions, manage the patient as
clinically appropriate (e.g. antihistamines, oxygen, fluids,
opioids, corticosteroids, bronchodilators, etc.) per investigator/
institutional guidelines
✓Refer to allergist to
prevent potential future
reactions
4 Life-threatening consequences; urgent
intervention indicated
CARDIOVASCULAR Specialist referral?
Grade CTCAE Description Management
1 Abnormal cardiac biomarker testing,
including abnormal ECG
•Recommend baseline ECG and cardiac biomarker assessment
(BNP, troponin) to establish if there is a notable change during
therapy
•Mild abnormalities should be observed closely during therapy
✓
if abnormal
2 Abnormal screening tests with mild
symptoms
•Control cardiac diseases (e.g. heart failure, atrial fibrillation)
optimally
•Control cardiac disease risk factors proactively (including
hypertension, hyperlipidemia, discontinue smoking, and
monitor diabetes)
✓
3 Moderately abnormal testing or
symptoms with mild activity
•BNP > 500 pg/ml, troponin >99% institutional normal, new ECG
findings (QTc prolongation, new conduction disease, or ST-T
wave changes)
•Consider withholding ICI
○If a period of stabilization is achieved and definite cardiac
toxicity was not identified, it may be reasonable to consider
re-challenging the patient with ICI, with heightened
monitoring.
✓
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Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•If confirmed cardiac injury or decompensation, hold ICI therapy
until stabilized.
•Optimally treat identified cardiac conditions
•Consider corticosteroids if myocarditis suspected (Note 2)
4 Moderate to severe decompensation,
intravenous medication or intervention
required, life threatening conditions
•Permanently discontinue ICI
•If myocarditis is identified, consider high-dose corticosteroids
(1 mg/kg methylprednisolone (IV) for at least several days) until
improved to grade ≤1, after that consider at least 4–5 weeks
of tapering doses (Note 2).
•Add additional immunosuppressive agents in severe refractory
cases.
•Give additional supportive treatments, including appropriate
treatment of heart failure. Additional treatment of detected
cardiac conditions should be provided.*
✓
Notes:
1. Grades outlined here are not drawn from CTCAE.
2. Patients with confirmed myocarditis (or in cases of reasonable suspicion) should receive emergent high-dose corticosteroids. Until data are
available (e.g., cut-off levels of troponin) to determine when to start corticosteroids in patients with possible (as opposed to confirmed)
myocarditis, this decision should be made on a case by case basis. The importance of active, ongoing consultation with a cardiologist to discuss
the risk/benefit of continuing ICI therapy, starting corticosteroids, or instituting other cardiac treatments, cannot be overstated.
* Other therapies for management of myocarditis or pericarditis (viral based therapy, immunoglobulins, or plasmapheresis) are speculative at this
point in time.
HEMATOLOGIC Specialist referral?
Anemia
Grade CTCAE Description Management
1 Hgb < LLN - 10.0 g/dL; <LLN - 6.2 mmol/L;
<LLN - 100 g/L
•Monitor closely while continuing ICI
2 Hgb <10.0–8.0 g/dL; <6.2–4.9 mmol/L;
<100 - 80 g/L
•Monitor closely while continuing ICI
•Evaluate for possible causes and refer to hematology if no
obvious cause if identified
✓
if no cause identified
3 Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L;
transfusion indicated
•Hold ICI
•Consider Coombs testing and evaluation for hemolytic anemia
•Consider re-treating with ICI if hemolytic anemia responds
promptly (within a few days) to corticosteroids
✓
4 Life-threatening consequences; urgent
intervention indicated
•Permanently discontinue ICI ✓
Notes:
1. No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
2. If unexplained anemia does not respond to steroids, consider bone marrow biopsy.
Thrombocytopenia (CTCAE defines decreased platelet count not thrombocytopenia)
Grade CTCAE Description Management
1 <LLN - 75,000/mm3; <LLN-75.0 x 10e9 /L •Progressive or grade 3 unexplained thrombocytopenia: consider
work up for autoimmune disease and rule out DIC or other
cause of thrombocytopenia that may be related to underlying
disease
•Precipitous development of thrombocytopenia: consider steroid
intervention pending clinical condition (brain metastases,
colitis, etc.) and evaluate for immune-mediated
thrombocytopenia
•Permanently discontinue ICI for clinically significant, steroid-
refractory ICI-associated thrombocytopenia
2 <75,000–50,000/mm3; <75.0–50.0 x 10e9 /L ✓
if no cause identified
3 <50,000–25,000/mm3; <50.0–25.0 x 10e9 /L ✓
4 <25,000/mm3; <25.0 x 10e9 /L ✓
Note: No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
RENAL Specialist referral?
Nephritis
Grade CTCAE Description Management
1 Creatinine level increase of >0.3 mg/dL;
creatinine 1.5–2.0× above baseline
•Continue ICI but initiate work-up to evaluate possible causes
and monitor closely
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 13 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
2 Creatinine 2 - 3× above baseline •Hold ICI
○Resume when creatinine decreased to ≤grade 1 (Note 2)
•Consider timing of event and response to treatment when
making a decision
•Start corticosteroids (Note 3)
•Discontinue ICI for persistent or recurrent elevation
3 Creatinine >3 x baseline or >4.0 mg/dL;
hospitalization indicated
•Hold ICI
•Consider resuming treatment if grade 3 resolves (Note 2) and
cause of event is confirmed. Timing of event and response to
treatment should be considered in making a decision
•Start corticosteroids (Note 3)
•Discontinue ICI for persistent or recurrent elevation
4 Life-threatening consequences; dialysis
indicated
•Permanently discontinue ICI
•Start corticosteroids (Note 3)
✓
Notes:
1. Grades are those listed under ‘acute kidney injury’in CTCAE [33].
2. Consider using increase from baseline rather than absolute value for creatinine monitoring, especially in patients with primary renal carcinoma or
other baseline renal conditions.
3. For persistent creatinine elevation ≥grade 2 with no other identifiable cause, start corticosteroids. Dose and schedule should be individualized
and based on grade. Taper corticosteroids when creatinine improves to grade 1.
NEUROLOGIC Specialist referral?
Encephalopathy/Leukoencephalopathy/Reversible posterior leukoencephalopathy syndrome (PRES)
Grade CTCAE Description Management
1 Mild symptoms •Hold ICI and initiate diagnostic work-up
•Consider permanent discontinuation of ICI if AE worsens or
does not improve
2 Moderate symptoms; limiting instrumental ADL •Hold ICI
•Start 0.5–1.0 mg/kg/day methylprednisolone equivalents PO or
IV once infection has been excluded
•Consider permanent discontinuation of ICI if AE worsens or
does not improve.
✓
3 Severe symptoms; limiting self-care ADL •Permanently discontinue ICI
•Start 1–2 mg/kg/day methylprednisolone equivalents IV and
prophylactic antibiotics
•Consider plasmapheresis if no improvement or symptoms
worsen after 3 days
✓
4 Life-threatening consequences; urgent
intervention indicated
•Permanently discontinue ICI
•Start 1–2 mg/kg/day methylprednisolone equivalents IV and
prophylactic antibiotics
•Consider plasmapheresis if no improvement or symptoms
worsen after 3 days
•Contact intensive care unit
✓
and contact intensive
care unit
Notes: CTCAE provides grading criteria for encephalopathy, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (PRES). For
all these irAEs, ICI therapy may be continued for grade 1 irAEs. However, ≥grade 2 events require an ICI hold, and referral to neurology. For events
of ≥grade 3 severity, ICI should be permanently discontinued, IV corticosteroids administered, and plasmapheresis considered if there is no
improvement, or symptoms worsen, after 3 days.
Peripheral motor and sensory neuropathy
Grade CTCAE Description Management
1 See CTCAE for grade definitions for
each disorder
•Continue ICI
•Consider permanent discontinuation of ICI if AE worsens or
does not improve
2•Hold ICI
•Refer to neurology
•Consider permanent discontinuation of ICI if AE worsens or
does not improve
✓
3•Permanently discontinue ICI
•Start 1–2 mg/kg/day methylprednisolone equivalents IV, and
prophylactic antibiotics
✓
4
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 14 of 28

Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Notes: CTCAE provides grading criteria for peripheral motor neuropathy and sensory motor neuropathy. For all these irAEs, ICI therapy may be
continued for grade 1 irAEs. However, ≥grade 2 events require an ICI hold and referral to neurology. For events of ≥grade 3 severity, ICI therapy
should be permanently discontinued and IV corticosteroids administered.
OPHTHALMOLOGIC
Uveitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
•Continue ICI
•Ophthalmology referral within 1 week
•Start lubrication drops (artificial tears)
✓
2 Anterior uveitis; medical intervention
indicated
•Hold ICI
•Ophthalmology referral within 2 days, prior to initiating uveitis
treatment
•Coordinate treatment with ophthalmologist (topical
corticosteroids, cycloplegic agents, systemic corticosteroids)
✓
3 Posterior or pan-uveitis (Note 1) •Permanently discontinue ICI
•In carefully selected cases it may be appropriate to restart
treatment, cautiously, depending on severity, systemic
response to immunotherapy and ocular response to topical,
local or systemic prednisone (prescribed in coordination with
ophthalmologist)
•URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating treatment. Co-ordinate treatment with
specialists
•Consider systemic corticosteroids in addition to intravitreal/
periocular corticosteroids/topical corticosteroid treatment as
recommended by ophthalmologist
✓
URGENT
4 Blindness (20/200 or worse) in the
affected eye
•Permanently discontinue ICI
•URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating any treatment. Co-ordinate treatment with
specialists
•Consider systemic corticosteroids in addition to intravitreal
/periocular corticosteroids/topical corticosteroid treatment as
recommended by ophthalmologist
✓
URGENT
Note: Unlike anterior uveitis, posterior uveitis can be asymptomatic but nonetheless proceed to visual loss.
Episcleritis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
•Continue ICI
•Ophthalmology referral within 1 week
•Start lubrication drops (artificial tears)
✓
2 Symptomatic, limiting instrumental ADL;
moderate decrease in visual acuity
(20/40 or better)
•Hold ICI
•Ophthalmology referral within 2 days, prior to initiating uveitis
treatment
•Coordinate treatment with ophthalmologist (topical steroids,
cycloplegic agents, systemic steroids) (See Note)
✓
3 Symptomatic, limiting self- care ADL;
marked decrease in visual acuity
(worse than 20/40)
•Permanently discontinue ICI
•In carefully selected cases it may be appropriate to restart
treatment, cautiously, depending on severity, systemic
response to immunotherapy and ocular response to topical,
local or systemic prednisone (prescribed in coordination with
ophthalmologist)
•URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating treatment (See Note). Co-ordinate treatment
with specialists.
•Consider systemic steroids in addition to intravitreal /periocular
steroids /topical steroid treatment as recommended by
ophthalmologist
✓
URGENT
4 Blindness (20/200 or worse) in the
affected eye
•Permanently discontinue ICI
•URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating any treatment (See Note). Co-ordinate
treatment with specialists.
✓
URGENT
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 15 of 28

should undergo full skin and mucosal exam, taking note
of the extent and type of lesions present.
When to refer In cases of non-urgent or emergent refer-
ral, photographic documentation is recommended when a
new dermatologic manifestation appears, prior to imple-
menting treatment. This facilitates later classification of the
AE when necessary. A same-day dermatology consult is
warranted in any patient with blisters covering ≥1% body
surface area (BSA), a rash with mucosal involvement, any
rash covering ≥30% BSA, and rash with skin pain with or
without blisters (excluding dermatomal varicella zoster).
For these latter cases, skin biopsy is recommended to help
classify the event. Non-acute dermatology referral is rec-
ommended for rashes where diagnosis is unclear, grade 2
rash that is worsening, erythema multiforme, blistering dis-
orders of any BSA or for a rash consistent with psoriasis or
lichenoid dermatitis that has not responded to topical
intervention. Any grade 3 dermatologic toxicity warrants a
same-day dermatology consult. Patients with suspected
SJS/TEN, severe mucocutaneous reactions characterized
by epidermal necrosis and detachment, should be hospital-
ized immediately and a dermatologist consulted for admin-
istration of systemic immunosuppression.
The recommended management of common dermato-
logic irAEs is presented in Table 3; recommendations for
managing uncommon dermatologic irAEs is presented
in Additional file 1:Table S1.
Gastrointestinal adverse events
Clinical presentation and epidemiology
Colitis
Diarrhea is one of the most frequently reported irAEs in
patients taking ICIs. Mild, transient, self-limited diarrhea
that occurs on initiation of an immune response should
be distinguished from other presentations. Onset occurs
after an average of three infusions [11], although it may
occcur as soon as following the first infusion. Incidence is
higher among patients taking combination anti-CTLA-4/
anti-PD-1 therapy (44%) than those receiving anti-CTLA-
4(23–33%) or anti-PD-1 (≤19%) monotherapy. The com-
binatorial approach is also associated with increased risk
of grade 3/4 symptoms compared with monotherapy, and
the proportion of patients experiencing high-grade symp-
toms is greater with ipilimumab than anti-PD-1 or anti-
PD-L1 agents [15, 40, 41]. The presence of diarrhea in
conjunction with abdominal pain, rectal bleeding, mucus
in the stool, and fever should alert the clinician to the
possibility of colitis, a potentially serious or even life-
threatening gastrointestinal (GI) complication of ICI ther-
apy. Reports differ on the primary location of ICI colitis,
with some finding a uniform distribution [42], and others
observing that inflammation preferentially affects the
descending colon [43, 44], although this may be due to
less frequent examination of the proximal colon [44, 45].
Diarrhea and/or colitis may recur months after discon-
tinuation of immunotherapy and can mimic chronic in-
flammatory bowel disease (IBD) [42, 46].
Hepatitis
Less frequently observed, but nonetheless well-recognized
in patients treated with ICIs, is a typically asymptomatic
immune-related hepatitis characterized by elevated ala-
nine aminotransferase (ALT) or aspartate aminotransfer-
ase (AST), with or without raised bilirubin. Median onset
of transaminase elevation is approximately 6–14 weeks
after starting ICI treatment [28]. A minority of patients
present with fever. The incidence of any-grade hepatic en-
zyme disturbance with ipilimumab 3 mg/kg monotherapy
is <4% and up to 15% when dosed at 10 mg/kg [24, 47].
Incidence of hepatitis in patients treated with anti-PD-1
ICIs is approximately 5%, but this rises to 30% in
patients treated with combination ipilimumab and
nivolumab [13, 28].
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
•Consider systemic steroids in addition to intravitreal /periocular
steroids /topical steroid treatment as recommended by
ophthalmologist
Notes: IMPORTANT: Starting treatment with steroids prior to conducting an eye exam may worsen ocular conditions that are due to infection (e.g.,
herpetic keratitis/uveitis) or may mask accurate diagnosis and severity grading when the patient is examined by an ophthalmologist.
Blepharitis
Grade CTCAE Diagnosis Management
Not defined in CTCAE •Puffy eyelids may indicate early preseptal cellulitis, which
requires systemic antibiotic treatment. Warning signs (eyelid
swelling with pain and erythema, proptosis, pain with eye
movements, movement restriction/diplopia, vision changes)
should prompt urgent ophthalmology referral
•In the absence of warning signs, start warm compresses and
lubrication drops and refer to ophthalmology, especially if
symptoms do not improve
✓
URGENT if warning
signs
[Note: Recommended management of uncommon dermatologic immune-related adverse events is presented in Additional file 1: Table S1]
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 16 of 28

Acute pancreatitis has been reported but is rare [42];
asymptomatic elevation of lipase and amylase are more
common. The role of the gut microbiome in determin-
ing treatment response and risk of toxicities, including
colitis, in patients treated with ICIs is an area of active
investigation.
Diagnostic evaluation
In the setting of acute diarrhea, initial evaluation should
exclude an infectious etiology (consider stool culture,
Clostridium difficile, cytomegalovirus (CMV) DNA poly-
merase chain reaction (PCR), stool ova and parasites).
Inflammatory markers (fecal leukocytes/lactoferrin, fecal
calprotectin) and fecal occult blood test (FOBT) may
help indicate whether there is an inflammatory process
underlying the diarrhea. Screening tests for tuberculosis,
human immunodeficiency virus (HIV) and hepatitis A
and B should be considered if there is potential for use
of systemic immunosuppression e.g. infliximab in the
near future. Based on the IBD literature, risk of hepatitis
C exacerbation is minimal; as a result, testing for hepa-
titis C is not recommended [48, 49].
Colitis
Radiologically, two distinct patterns of anti-CTLA-4-as-
sociated colitis have been observed on computed tomog-
raphy (CT) imaging: a more common diffuse colitis
characterized by mesenteric vessel engorgement, and a
segmental colitis with moderate wall thickening and
associated pericolonic fat stranding in a segment of pre-
existing diverticulosis [50]. A fluorodeoxyglucose positron
emission tomography (FDG-PET)/CT study can also dem-
onstrate new FDG-avid diffuse colonic wall thickening in
patients with immune-related colitis [50]. Colonoscopy is
the most accurate means of evaluating the extent and se-
verity of colitis and is recommended in appropriate cases
since recent data suggest that the presence of ulceration
on endoscopy predicts steroid-refractory disease [51]. For
grade ≥2 diarrhea, systemic immunosuppression should
be initiated promptly after ruling out infectious etiology.
Colonoscopy can be considered if deemed clinically neces-
sary, although it is worth noting that certain types of
colitis may have a normal endoscopic appearance,
with significant inflammatory features on histology.
Therefore, routine mucosal biopsies should be per-
formed for histological examination. In addition, path-
ology with immunohistochemical staining to rule out
CMV infection is critical.
Histologically, colitis that follows treatment with anti-
CTLA-4 antibodies is characterized by neutrophilic in-
flammation with increased intraepithelial lymphocytes,
crypt epithelial cell apoptosis and few or no features of
chronicity. Similarly, anti-PD-1-related colitis typically
follows one of two patterns: active colitis with apoptosis
(active inflammation, neutrophilic crypt micro-abscesses,
increased crypt epithelial cell apoptosis, and presence of
crypt atrophy/dropout) or lymphocytic colitis (increased
intraepithelial lymphocytes in surface epithelium, surface
epithelial injury, and expansion of the lamina propria).
Pathological changes may also be visible outside the colon
in the duodenum, stomach and/or small bowel [52].
Hepatitis
Liver function testing prior to initiation of ICIs, and
again before each cycle of treatment, can help determine
patterns of liver enzyme disturbance. Hepatitis following
ICI therapy is typically detected on routine serum liver
function tests. Other causes of liver damage such as viral
infection, alcohol, other medications or cancer progres-
sion should be excluded. Other thromboembolic and
outflow obstructive etiology should also be excluded
through imaging. On radiologic evaluation, ipilimumab-
associated hepatitis has been shown to present with
non-specific and variable findings according to clinical
severity [53]. Hepatomegaly, edema and enlarged lymph
nodes in the periportal region, and attenuated liver paren-
chyma may be evident on CT and MRI. Liver biopsy, only
necessary in complicated cases, may reveal predominantly
hepatocyte injury (acute hepatitis pattern) with sinusoidal
histiocytic infiltrates, central hepatic vein damage and
endothelial inflammation similar to autoimmune hepatitis,
or predominant bile duct injury (biliary pattern, with por-
tal inflammation) [53, 54]; rarely, fibrin ring granulomas
have also been reported [55].
When to refer
If infectious work-up is negative, diarrhea due to previous
immunotherapy exposure should be considered a possible
etiology since colitis can wax and wane after an initial epi-
sode. Endoscopy and histology may provide further clarifi-
cation, and the patient should be referred promptly to a
gastroenterologist who is experienced managing patients
with gastrointestinal adverse events after immunotherapy.
There are reports about progression of colitis to chronic
IBD long term [56] and such patients should be followed
by a gastroenterologist long term.
Endocrine adverse events
Clinical presentation and epidemiology
The two most common endocrine irAEs are acute hypophy-
sitis resulting in hypopituitarism (central hypothyroidism,
central adrenal insufficiency, hypogonadotropic hypogonad-
ism), and thyroid disease or abnormalities in thyroid func-
tion tests (primary hypothyroidism and thyroiditis). Other
endocrinopathies such as primary adrenal insufficiency,
T1DM, hypercalcemia, and hypoparathyroidism have
been reported but are rare. The prevalence of these disor-
ders varies greatly. This may be due to the non-specific
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 17 of 28

presenting signs and symptoms, such as, headache, fatigue,
anorexia and nausea, coupled with the fact that hormonal
abnormalities are not uncommon in patients with advanced
cancer. Diagnosis is also complicated by the fact that base-
line screening for endocrine abnormalities is not routinely
performed (other than thyroid function tests, in some
cases), and corticosteroids may be initiated empirically
for suspected irAEs, which interferes with subsequent
endocrine testing. A low threshold of clinical suspi-
cion is therefore warranted and, in the absence of al-
ternateetiologies,adiagnosticwork-upforendocrine
dysfunction should be initiated.
Diagnostic evaluation
Routine monitoring for clinical signs and symptoms of
endocrinopathies, and patient education, are recom-
mended. All patients should be tested before starting treat-
ment for thyroid (thyroid-stimulating hormone [TSH]
and free thyroxine [freeT4]), early morning adrenal
(adrenocorticotropic hormone [ACTH] and cortisol)
function, and glycemic control (glucose and glycated
hemoglobin [HbA1c]). In situations where new elevation
in glucose is noted, testing for blood or urinary ketones
should be considered. Before each cycle, thyroid testing
TSH and free T4) should be repeated, along with a base-
line metabolic panel to allow monitoring of glycemic
trends.. Routine monitoring with early morning ACTH
and cortisol levels should be considered (every month for
6 months, then every 3 months for 6 months then every
6 months for 1 year).
Hypophysitis
Hypophysitis is most commonly seen with anti CTLA-4
antibody monotherapy (ipilimumab, with an incidence
of ≤10% at a dose of 3 mg/kg and up to 17% at
10 mg/kg), and with combination ipilimumab/nivolumab
(incidence ≤13%) [10, 13, 16, 17, 57]. The median time
from starting ipilimumab to diagnosis of hypophysitis is
8–9 weeks, or after the third dose of ipilimumab [15, 58].
Symptoms commonly include headache (85%) and fatigue
(66%); visual changes are uncommon. Clinical suspicion of
hypophysitis is frequently raised when routine thyroid
function testing shows a low TSH with low free T4,
suggestive of a central etiology. Patients have various
degrees of anterior pituitary hormonal deficiency, with
central hypothyroidism being most commonly seen
(>90%), followed by central adrenal insufficiency, which is
also found in the majority of patients [59–61]. Both
central hypothyroidism and adrenal insufficiency occur
in >75% of patients and approximately 50% of patients
present with panhypopituitarism (adrenal insufficiency
plus hypothyroidism plus hypogonadism) [61–63]. On
magnetic resonance imaging (MRI) of the sella, pituitary
enlargement can precede the development of clinical and
biochemical evidence of disease. MRI abnormalities, such
as stalk thickening, suprasellar convexity, heterogeneous
enhancement, and increased height of the gland as com-
pared with baseline scans (when available) are present in
most patients at the time of diagnosis. Resolution of pitu-
itary enlargement is common, with all cases resolved on
follow up scans after two months [60, 64].
All patients with suspected hypophysitis based on clin-
ical findings (headache, fatigue) or biochemical evalu-
ation (routine thyroid function testing showing low free
T4 with low/normal TSH) should undergo further test-
ing for diagnostic confirmation. Recommended tests,
preferably conducted in the morning around 8 am, in-
clude thyroid function (TSH, free T4), adrenal function
(ACTH, cortisol or 1 mcg cosyntropin stimulation test),
gonadal hormones (testosterone in men, estradiol in
women), follicle-stimulating hormone [FSH], luteinizing
hormone [LH]) and MRI of the sella, with pituitary cuts.
This should be done prior to administration of steroids.
Strict criteria for diagnostic confirmation of hypophysitis
are not currently available. Proposed confirmation cri-
teria include ≥1 pituitary hormone deficiency (TSH or
ACTH deficiency required) combined with an MRI ab-
normality, or ≥2 pituitary hormone deficiencies (TSH or
ACTH deficiency required) in the presence of headache
and other symptoms.
Management of confirmed hypophysitis includes re-
placement of deficient hormones (physiologic doses of ste-
roids and thyroid hormone). In the presence of both
adrenal insufficiency and hypothyroidism, steroids should
always be started prior to thyroid hormone in order to
avoid an adrenal crisis. High doses of steroids are necessary
in the setting of severe headaches, vision changes or ad-
renal crisis. Both adrenal insufficiency and hypothyroidism
appear to represent long term sequelae of hypophysi-
tis and lifelong hormonal replacement is needed in
most cases [59, 64–66]. All patients with adrenal in-
sufficiency should be instructed to obtain and carry a
medical alert bracelet.
Thyroid dysfunction
Thyroid dysfunction (hypothyroidism, hyperthyroidism,
and thyroiditis) was reported in 6–20% of patients in
large phase 3 clinical trials.
Hypothyroidism
Patients with unexplained fatigue, weight gain, hair loss,
cold intolerance, constipation, depression and other rec-
ognized symptoms should be suspected of having
hypothyroidism. Lab tests showing high TSH and low
free T4 are indicative of biochemical hypothyroidism
and, if present, additional testing for thyroid antibodies
such as thyroid peroxidase (TPO) antibody is warranted.
Patients with confirmed hypothyroidism should be started
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 18 of 28

on thyroid hormone, with repeat TSH and free T4 levels
evaluated 6–8 weeks later. Once a maintenance dose is
identified (TSH within normal range) clinical and biochem-
ical re-evaluation should be undertaken every 12 months.
Thyrotoxicosis
Thyrotoxicosis (high free T4 or total T3 with low or nor-
mal TSH) may occur secondary to thyroiditis or Graves’
disease. Thyroiditis is the most frequent cause of thyrotoxi-
cosis and is seen more commonly with anti-PD1/PD-L1
drugs than with anti-CTLA-4 agents; Graves’disease is
very rare and occurs more commonly with anti-CTLA-4
drugs. Thyrotoxicosis due to thyroiditis may present with
weight loss, palpitations, heat intolerance, tremors, anxiety,
diarrhea and other symptoms of hypermetabolic activity,
although these symptoms may be masked if the patient is
taking beta-blockers. Most commonly, patients are asymp-
tomatic (painless thyroiditis) and routine laboratory moni-
toring shows high free T4 or triiodothyronine (T3) levels,
with low/normal TSH. A thyrotoxic phase occurs an aver-
age of one month after starting the drug. Additional tests
can be undertaken when thyroiditis is suspected, primarily
to rule out other causes of thyrotoxicosis such as Graves’
disease. These include thyroid stimulating hormone recep-
tor antibody [TRAb] or thyroid stimulating immunoglobu-
lin (TSI) and TPO as well as images when feasible:
radioactive iodine uptake scan (RAIUS) or Technetium
(Tc)-99 m [pertechnetate] thyroid scan if recent iodinated
contrast was used. Thyroiditis is a self-limiting process and
leads to permanent hypothyroidism after an average
of 1 month after the thyrotoxic phase and 2 months
from initiation of immunotherapy. Conservative manage-
ment during the thyrotoxic phase of thyroiditis is sufficient.
Non-selective beta blockers, preferably with alpha receptor-
blocking capacity, may be needed in symptomatic patients.
Repeat thyroid hormone levels should be performed every
2–3 weeks and thyroid hormone replacement initiated at
thetimeofhypothyroidism diagnosis [59, 64].
Type 1 diabetes mellitus
Development of polyuria, polydipsia, weight loss, nausea
and/or vomiting should prompt investigation for possible
development or worsening of T1DM. Diagnosis and
management of T1DM is based on recognized guidelines
[67]. Tests for antibodies (glutamic acid decarboxylase
[GAD65], anti-insulin, anti-islet cell A, zinc transporter 8
[Zn-T8]), C-peptide and insulin could distinguish between
type 1 and type 2 disease.
When to refer
An endocrinology consultation is recommended in all
cases of suspected or confirmed hypophysitis, primary
hypothyroidism, hyperthyroidism, thyroiditis, type 1 DM
and all rare endocrinopathies.
Pulmonary adverse events
Clinical presentation and epidemiology
Pneumonitis
The most common lung toxicity observed in patients re-
ceiving ICI treatment is pneumonitis. The overall inci-
dence of pneumonitis associated with PD-1/PDL-1 and
CTLA-4-targeted therapies is <5%, with high-grade
(≥grade 3) events occurring in 1–2% of patients. Higher
rates have been reported for combinations of PD-1 and
CTLA-4 inhibitors [68]. These numbers are not clinic-
ally trivial, as pneumonitis is one of the most common
causes of ICI-related death. Moreover, the incidence of
pneumonitis is increasing as therapeutic indications for
ICIs expand, and more complex regimens are developed.
Pneumonitis may present on imaging studies as crypto-
genic organizing pneumonia (COP), nonspecific interstitial
pneumonitis (NSIP), hypersensitivity pneumonitis (HP), or
usual interstitial pneumonitis (UIP)/pulmonary fibrosis
(PF). Clinical and radiographic findings of ICI-related pneu-
monitis may closely mimic pneumonia, lymphangitic
spread of disease, cancer progression, and diffuse alveolar
hemorrhage. The radiographic appearance of pneumonitis
may be clinically asymptomatic or, alternatively, associated
with new or worsening shortness of breath, cough, wheez-
ing, chest pain, reduced exercise tolerance, fatigue with ac-
tivities of daily living (ADL) and new or increasing
requirement for supplementary oxygen. Acuity of onset
and severity may also vary, suggesting the importance of
vigilance and rapid response in some cases. Studies have
suggested a higher incidence of any grade (3.6% vs. 1.3%)
and severe (1.1% vs. 0.4%) pneumonitis with PD-1 inhibi-
tors compared with PD-L1 inhibitors [69]. Combination
therapies with anti-CTLA-4/anti-PD-1/PD-L1 immuno-
therapy and with ICI/cytotoxic combinations also confer a
higher risk of pneumonitis versus ICI monotherapy
[68, 70]. Higher rates of pneumonitis have also been re-
ported among ICI-treated patients with non-small cell lung
cancer (NSCLC) compared to patients with melanoma
[71]. Pneumonitis onset appears earlier in cases of NSCLC
(median [range]: 2.1 [0.2–27.4] months) versus melanoma
(median [range]: 5.2 [0.2–18.1] months) [72]. IrAEs associ-
ated with other organ systems, including hepatitis, colitis,
duodenitis, esophagitis, thyroiditis, hypophysitis, arthritis,
myositis, vitiligo, nephritis, and anemia may occur in up to
50% of patients and confound therapy. These irAEs may
occur concomitantly, precede or follow the development of
pneumonitis. In patients with preexisting lung diseases,
such as chronic obstructive pulmonary disease (COPD) or
PF, the diagnosis of pneumonitis is particularly challenging
and failure to recognize and treat pneumonitis in a timely
manner could lead to poor clinical outcomes.
In addition to pneumonitis, ICI therapy has been associ-
ated with pleural effusions, pulmonary sarcoidosis and
sarcoid-like granulomatous reactions. Sarcoid-like reactions
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 19 of 28

have been reported following both CTLA-4 and PD-1/PD-
L1-targeted therapies. Increased numbers of T helper 17
(Th17.1) cells </