Contents · Table 1A Neuro Cardiac Pulmonary Renal GI Endocrine Miscellaneous Notes Encephalopathy...
27
Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 16 Melvin J. Rivera, Bryan Do, Jeffrey C. Bryan, Terri Lynn Shigle, and Rina Patel Contents Introduction ............................................................................ 202 Toxicities of Anticancer Therapy ..................................................... 202 References .............................................................................. 217 Abstract Advances in the management of hematologic malignancies and solid tumors have given rise to diverse modalities to treat cancer other than cytotoxic chemotherapy, including targeted therapies, immunotherapies, and cellular ther- apies. Currently, there are over 175 FDA-approved antineoplastic agents in the United States, many with a diverse and profound toxicity profile. Complications of antineoplastic therapy may result in the need for intensive care unit (ICU) admission to pro- vide acute symptom management. Accord- ingly, ICU providers caring for cancer patients should have a working knowledge of the toxicities and complications associated with antineoplastic therapy. Keywords Chemotherapy · Immunotherapy · Cancer · Toxicity · Oncology · Critical care · Intensive care · Complications · Adverse effects · Antineoplastic agents M. J. Rivera Thoracic / Head and Neck Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] B. Do Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] J. C. Bryan Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] T. L. Shigle Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] R. Patel (*) Critical Care / Nutrition Support, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 J. L. Nates, K. J. Price (eds.), Oncologic Critical Care, https://doi.org/10.1007/978-3-319-74588-6_21 201
Transcript of Contents · Table 1A Neuro Cardiac Pulmonary Renal GI Endocrine Miscellaneous Notes Encephalopathy...
Complications and ToxicitiesAssociated with Cancer Therapiesin the Intensive Care Unit
16
Melvin J. Rivera, Bryan Do, Jeffrey C. Bryan,Terri Lynn Shigle, and Rina Patel
ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Toxicities of Anticancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
AbstractAdvances in the management of hematologicmalignancies and solid tumors have given riseto diverse modalities to treat cancer other thancytotoxic chemotherapy, including targetedtherapies, immunotherapies, and cellular ther-apies. Currently, there are over175 FDA-approved antineoplastic agents inthe United States, many with a diverse andprofound toxicity profile. Complications ofantineoplastic therapy may result in the needfor intensive care unit (ICU) admission to pro-vide acute symptom management. Accord-ingly, ICU providers caring for cancerpatients should have a working knowledge ofthe toxicities and complications associatedwith antineoplastic therapy.
KeywordsChemotherapy · Immunotherapy · Cancer ·Toxicity · Oncology · Critical care · Intensivecare · Complications · Adverse effects ·Antineoplastic agents
M. J. RiveraThoracic / Head and Neck Medicine, The University ofTexas MD Anderson Cancer Center, Houston, TX, USAe-mail: [email protected]
B. DoLymphoma and Myeloma, The University of Texas MDAnderson Cancer Center, Houston, TX, USAe-mail: [email protected]
J. C. BryanLeukemia, The University of Texas MD Anderson CancerCenter, Houston, TX, USAe-mail: [email protected]
T. L. ShigleOncology, The University of Texas MD Anderson CancerCenter, Houston, TX, USA
Stem Cell Transplantation and Cellular Therapy, TheUniversity of Texas MD Anderson Cancer Center,Houston, TX, USAe-mail: [email protected]
R. Patel (*)Critical Care / Nutrition Support, The University of TexasMD Anderson Cancer Center, Houston, TX, USAe-mail: [email protected]
© Springer Nature Switzerland AG 2020J. L. Nates, K. J. Price (eds.), Oncologic Critical Care,https://doi.org/10.1007/978-3-319-74588-6_21
201
Introduction
The prevalence of cancer has grown tremendouslyand with that so has the need for new orrepurposed anticancer therapies. Advances in themanagement of hematologic malignancies andsolid tumors have given rise to diverse modalitiesto treat cancer other than cytotoxic chemotherapy,including targeted therapies, immunotherapies,and cellular therapies. There are over175 approved antineoplastic agents in the UnitedStates and more in development with unique tox-icity profiles [163]. This has created a uniqueopportunity for critical care specialists to managecomplications of critically ill cancer patientsreceiving anticancer therapies.
Toxicities of Anticancer Therapy
Tables 1A–H provides a list of antineoplasticagents and toxicities that may necessitate a higherlevel of care and/or impact care within the intensivecare unit (ICU). These tables are not all-inclusive ofevery minor adverse effect of each agent. Instead,they focus on toxicities that are considered severe/life-threatening complications or clinically relevant(e.g., grade 3 or 4 adverse effects). Agents that didnot meet the criteria for addition to Tables 1A–Hinclude the following: azacitidine, cladarabine,decitabine, elotuzumab, hydroxyurea, ixazomib,lomustine, olaratumab, omacetaxine, procarba-zine, talimogene, valrubicin, and venetoclax.
202 M. J. Rivera et al.
Tab
le1A
Neuro
Cardiac
Pulmon
ary
Renal
GI
End
ocrine
Miscellaneou
sNotes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
PericardialeffusionsSeverehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
PleuraleffusionsOrganizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
PancreatitisHepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
5-Fluorouracil(5-FU)
XX
XX
XX
See
Note1
Abemaciclib
XX
See
Note2
Acalabrutinib
XX
XX
See
Note3
Ado-trastuzum
abX
XX
XX
See
Note4
Afatin
ibX
XX
XX
See
Note5
Aflibercept
XX
XX
XX
See
Note6
Aldesleuk
inX
XX
XX
XSee
Note7
Alectinib
XX
XX
XSee
Note8
Alemtuzumab
XSee
Note9
1Cases
ofhyperammonem
icencephalopathy
have
occurred
with
in72
hof
infusion
initiation.Mostcases
ofhyperammonem
icencephalopathy
aretreatedwith
ammon
ialoweringtherapies.
Cases
ofacutecerebellarsyndromehave
also
been
reported.H
igherincidenceof
cardiactoxicity
with
infusion
vsbolusdosing
of5F
U[60,
149,
151,
238]
2Delayed
hepatotoxicity(A
LTandASTelevations
ofgrade3or
greater)with
medianonset2–6
months,generally
resolvingto
lessthan
grade3in2weeks
with
dose
interruptio
n,reduction,
discon
tinuatio
n,or
delay[137
,225]
3Atrialfi
brillationandfluttercanoccur.PJP
prophylaxisandCMVmonito
ring
arerecommended.Major
hemorrhagehasbeen
reported
with
BTKinhibitors.C
onsiderwith
holding3–
7days
priorto
procedures
dependingon
risk
ofbleeding
[13,
41]
4GI,CNS,and
pulm
onarybleeding
have
occurred
intrialswith
somefatalities.Higherriskinpatientson
anticoagulantsor
antip
latelettherapy.L
iverfailu
re,hepaticencephalopathy,idiopathic
noncirrhoticpo
rtalhy
pertension
,and
deathhave
been
reported
[82]
5Hepaticim
pairmentisrare
butfatalities
have
been
repo
rted.D
iarrheacanbe
severe
andmay
lead
todehy
drationandsubsequent
renalfailure
[31]
6Hypertensiononsetisgenerally
with
inthefirsttwocycles.P
roteinuria,n
ephroticsyndrome,andTMAhave
been
associated
with
ziv-aflibercept
[210]
7High-do
seIL-2
hasablackbo
xwarning
forcapillaryleak
syndrome,CNStoxicity,and
increasedrisk
ford
isseminated
infection.Use
shou
ldbe
restricted
topatientswith
norm
alcardiacand
pulm
onaryfunctio
n.IL-2
shouldonlybe
administeredunderthe
supervisionof
anexperiencedcancerchem
otherapy
physicianinafacilitywith
ICUfacilitiesavailable.Consensus
guidelines
areavailableto
providecriteriaforsafe
administrationandtoxicity
managem
ent[66
,196]
8Sym
ptom
aticbradycardiacanoccur.Whentreatin
ghy
pertension
usecautionwhenadministering
antih
ypertensiveagentsthatcancausebradycardia.Severerenaleventsarerare
butfatal
caseshave
been
reported.T
hemajority
ofhepatotoxicityoccurswith
inthefirst3
mon
thsof
therapy.Mon
itorC
PKandforsigns
orsymptom
sof
musclepainor
weakn
ess.Mediantim
etograde
3CPKelevations
14days
[86]
9PJP
andHSVprophylaxisisrecommendedfrom
initiationof
treatm
entu
ntil2monthsfollo
winglastdose
oruntil
CD4+
>20
0/mm
3[91]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 203
Tab
le1B
Neuro
Cardiac
Pulmon
ary
Renal
GI
End
ocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
Pericardialeffusions
Severehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Arsenictrioxide
XX
XX
See
Note10
AsparaginaseErw
iniachrysanthemi
XX
XX
XSee
Note11
Atezolizum
abX
XX
XX
XX
XX
XX
XX
See
Note12
Avelumab
XX
XX
XX
XX
XX
XX
See
Note13
Axicabtageneciloleucel
XX
XX
XX
XX
XSee
Note14
Axitin
ibX
XX
XX
XX
XX
XSee
Note15
Belinostat
XSee
Note16
Bendamustin
eX
See
Note17
Bevacizum
abX
XX
XX
XX
XX
See
Note18
Bexarotene
XX
XSee
Note19
Bleom
ycin
XX
See
Note20
Blin
atum
omab
XX
XX
XSee
Note21
Bortezomib
XX
XX
XSee
Note22
Bosutinib
XX
See
Note23
Brentuxim
abvedo
tinX
XX
XX
XSee
Note24
Brigatin
ibX
XX
XX
See
Note25
Busulfan
XX
XX
See
Note26
Cabazitaxel
XX
XX
XSee
Note27
Cabozantin
ibX
XX
XX
XX
See
Note28
10Differentiatio
nsyndromeusually
occurs
during
thefirstcycleof
arsenic,
medianon
set17
days
(7–24days)andiscommonly
associated
with
thedevelopm
entof
hyperleuko
cytosis,
pulm
onaryedem
a,generalized
edem
a,headache,bone
pain,andrenalfailu
re.Managem
entincludes
steroids
and/or
discontin
uatio
nof
arsenicdependingon
severity.Alth
ough
QT
prolongatio
niswelldescribed,clin
icallysignificantarrhythm
iasarerarewhenappropriatelymon
itoredandmanaged
–maintainserumpo
tassiumlevelsabov
e4mEq/Landmagnesium
levels
abov
e1.8mg/dL
[201,2
15]
11Sim
ilarto
theotherasparaginase
form
ulations,pancreatitis,abnormaltransaminases,coagulatio
nabnorm
alities
includingthrombosisandhemorrhage,andhy
perglycemiacanoccur[115]
12May
causesevere
immune-mediatedadverseeventsincludingpn
eumonitis,medianon
set3
mon
ths(3
days
to18
.7mon
ths)andmediandu
ratio
n2–6weeks,upto
12.6mon
thsor
long
er;
severe
diarrhea,m
edianon
set3
–7weeks
(12days
to3.4mon
ths);h
epatitis,medianon
set1
mon
th;h
ypothy
roidism,m
edianon
set5
mon
ths(15days
to31
mon
ths);h
ypophy
sitis,rare,two
204 M. J. Rivera et al.
case
reports,onset12–13months.May
aggravateunderlying
autoim
munedisorders.Managem
entincludes
holdingtherapy,system
iccorticosteroids,+/�
additio
nalim
munosup
pressants
(e.g.,inflixim
ab,m
ycophenolate,and
vedolizum
ab).ConsiderPJP
prophylaxisin
patientswith
prolongedcorticosteroid
exposure
[33,
89,1
22,1
60]
13May
causesevereim
mune-mediatedadverseeventsincludingpneumonitis,medianonset2.5months(3
days
to11
month);hepatitis,m
edianonset3.2mon
ths(7
days
to15
months);colitis,
medianon
set2.1mon
ths(2
days
to11
mon
ths);adrenalinsufficiency,m
edianon
set2.5mon
ths;im
mun
e-mediatedthyroiddisorders,medianon
setfor
2.8mon
ths(2
weeks
to13
mon
ths).M
ayaggravateunderlying
autoim
munedisorders.Managem
entincludes
holdingtherapy,
system
iccorticosteroids,+/�
additio
nalim
munosup
pressants(e.g.,inflixim
ab,mycop
heno
late,and
vedolizum
ab).ConsiderPJP
prophylaxisin
patientswith
prolongedcorticosteroid
exposure
[33,
73]
14ICANS:M
edianon
set4
days
(1–43days);mediandu
ratio
nof
neurologictoxicities17
days.M
ostcom
mon
neurologicaltoxicities:encephalopathy,h
eadache,trem
or,d
izziness,aphasia,
delirium,insom
nia,andanxiety.Fatalandseriouscasesof
cerebraledem
ahave
occurred.O
ther
seriouseventsincluded
leukoencephalopathyandseizures
CRS:M
edianon
set2
days
(1–12days);mediandu
ratio
n7days
(2–58days).Key
manifestatio
nsof
CRS:fever,h
ypotension,tachycardia,h
ypoxia,and
chills
Managem
ento
fCRSdependson
gradingor
severity
butincludessupportiv
ecare,interleukin-2
receptor
antagonisttocilizum
ab,and/orsystem
iccorticosteroids
Grade
2or
high
erICANSwith
outC
RSshou
ldbe
treatedwith
supportiv
ecareand/or
system
iccorticosteroidsas
thereisinsufficientdatawith
tocilizum
abinthissetting.C
onsideranti-seizure
medicines
(e.g.,levetiracetam
)forseizureprop
hylaxisforanygrade2or
high
erneurolog
ictoxicities
Cardiac
arrhythm
ias(e.g.,atrialfibrillation,
ventriculartachycardia),cardiac
arrest,cardiac
failu
re,renalinsufficiency,capillaryleak
syndrome,HLH/M
AScanoccur
Hypogam
maglobulin
emiasecondaryto
B-cellaplasiamay
persistfor
upto
13monthsandincrease
therisk
forinfections.P
JPandHSVprophylaxisisrecommendedforatleast1
yearafter
CAR-T
celltherapy[128,1
61,2
21]
15Wound
healingcomplications
–ho
ldforatleast2
4hpriorto
surgeryandrestartw
henwou
ndhealed.R
PLSisrare
butserious.M
onito
rforheadache,seizure,lethargy,andhy
pertension
[187
]16QTprolon
gatio
nisaclasseffectof
HDACinhibitors,alth
ough
theincidencemay
belower
than
initially
reported.O
ptim
izeserum
potassium
andmagnesium
levels[205
,228]
17Severecutaneou
sreactio
nsinclud
ingSJS,T
EN,D
RESS,and
bullo
uspemph
igoidhave
been
repo
rted
[45,
131,
239]
18RPLS:on
setof
symptom
sfrom
16hto
1year
afterthefirstdo
se.Monito
rforheadache,seizure,
lethargy,andhy
pertension
.Wou
ndhealing:
ifpo
ssible
waitat
least4weeks
after
bevacizumab
discon
tinuatio
nformajor
surgicalprocedures
anddo
notrestartforat
least4weeks
aftersurgeryor
until
wou
ndisfully
healed.Cases
ofTMA
have
been
repo
rted.H
igher
incidenceof
GIperforationin
patientswith
previous
pelvicirradiation.
Severepulm
onaryhemorrhagereported
inNSCLC[30,
75,8
7,10
7,19
7,21
8]19Bexaroteneindu
cessign
ificantlip
idabno
rmalities,usuallyoccurringwith
in2–4weeks.Pancreatitisassociated
with
hypertriglyceridem
iahasbeen
reported.Interrupttreatm
entand
evaluate
ifpancreatitisis
suspected;
triglyceridesshould
bemaintained<400mg/dL
utilizing
HMG-CoA
reductaseinhibitors
orfenofibrate.
Gem
fibrozilis
notrecommendeddueto
increased
bexarotene
andtriglyceride
levels.B
exarotenerapidlysuppresses
TSHlevelsby
directly
inhibitin
gTSHsecretionandthyroidhorm
onemetabolism
[98,
236]
20Bleom
ycinmay
causepn
eumonitisleadingtopu
lmon
aryfibrosis.R
iskfactorsinclud
eage>70
years,cumulativelifetim
edose>45
0un
its,priormantle
radiation,renalimpairment,ox
ygen
exposure,smoking,
andgranulocyte-colony
stim
ulatingfactor
use[16,
37]
21Neurotoxicitiesincludetrem
ors,confusion,encephalopathy,aphasia,and
seizures,w
hich
arereversiblein
mostcases.O
nsetof
symptom
susually
occursarou
ndday7of
thefirstcycleof
treatm
ent.Managem
entincludestreatm
entw
ithdexamethasone,w
ithor
with
outblin
atum
omab
interrup
tion,andanti-seizuremedicationas
indicated.CRSismanaged
with
dexamethasone,
with
orwith
outb
linatum
omab
interruptio
n,andtocilizum
abas
indicated.
Hepatotoxicity
canpresentalone
orin
associationwith
CRS[7,2
42,2
43]
22New
onsetorexacerbationof
HF,pn
eumon
itis,andpu
lmon
aryhy
pertension
may
occur.Acuteliv
erfailu
reandRPLShave
been
reported
rarelywith
bortezom
ib.H
SV/VZVprophylaxisis
required
during
therapydueto
risk
ofreactiv
ation[150]
23Mostcom
mon
toxicitiesareGI(i.e.,diarrhea,n
ausea,andvo
miting
).Pleuraleffusion
smay
developin
patientswith
apriorhistoryof
pleuraleffusions
anddasatin
ibexposure
[125]
24Serious
andfatalcases
ofGIcom
plications
(i.e.,acutepancreatitis,hemorrhage,obstruction,perforation)
andhepatotoxicityhave
been
reported,w
ithhigh
erincidenceinpatientswith
GIo
rliv
erdiseaseinvo
lvem
ent.Cases
ofPMLanddeathdu
eto
JCvirusinfectionhave
occurred
with
medianon
seto
f7weeks
afterinitiation(3–34weeks)([48
],Seattle[217])
25Sym
ptom
aticbradycardiacanoccur.Whentreatin
ghy
pertension,use
cautionwhenadministering
with
antih
ypertensiveagentsthatcancausebradycardia.Higherincidence
andearliero
nset
ofpneumonitiscomparedtootherA
LKinhibitors.ILD/pneum
onitistypically
occurswith
in9days
ofinitiation–high
erincidencewith
180mg/dayvs
90mg/day.Mon
itorC
PKatbaselin
eand
period
ically
forsign
sor
symptom
sof
musclepain
orweakn
ess[9,1
27].
26Anti-seizureprophylaxisrequired
with
administrationof
busulfan.V
ODisarisk
amongpatientsreceivingbusulfan,but
theincidencehasdecreasedsincethetransitio
ninstandard
ofcare
from
oraltoIV
busulfan
andtheuseof
PKford
osing.Avoiduseof
acetam
inophen,metronidazole,orintroductionof
anymedicationthatmay
inhibit/induceCYPA
3A4foratleast72
hbefore,
during,and
for72
hafterbusulfan
administrationas
thesearemajor
drug
interactions
thatwill
affectPKdosing
[52,
181]
27Caserepo
rtsof
hemorrhagiccystitis,which
may
bedu
eto
radiationrecallin
patientswith
historyof
pelvicirradiation.
Highratesof
grade3/4neutropeniain
clinicaltrials[97,
141,
213]
28RPLShasoccurred
rarelyintrials.M
onito
rfor
headache,seizure,lethargy,andhy
pertension.C
anim
pairwou
ndhealing–ho
ld28
days
priortosurgeryandresumeon
cewou
ndhashealed
[76]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 205
Tab
le1C
Neuro
Cardiac
Pulmon
ary
Renal
GI
End
ocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
Pericardialeffusions
Severehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Capecitabine
XX
XX
XX
XX
XX
XSee
Note29
Carboplatin
XX
XSee
Note30
Carfilzom
ibX
XX
XX
XX
XSee
Note31
Carmustin
eX
See
Note32
Ceritinib
XX
XX
XX
XX
See
Note33
Cetux
imab
XX
See
Note34
Chloram
bucil
XX
See
Note35
Cisplatin
XX
XX
XX
See
Note36
Clofarabine
XX
XX
XX
See
Note37
Cob
imetinib
XX
XX
XSee
Note38
Cop
anlisib
XX
XX
See
Note39
Crizotin
ibX
XX
XX
See
Note40
Cyclophospham
ide
XX
XX
XX
XSee
Note41
Cytarabine
XX
XSee
Note42
Dabrafenib
XX
XX
XX
See
Note43
Dacarbazine
XSee
Note44
Dactin
omycin
XX
XSee
Note45
Daratum
umab
XX
See
Note46
Dasatinib
XX
XX
XX
XX
See
Note47
Daunorubicin
XSee
Note48
Daunorubicinandcytarabine
(liposom
al)
XSee
Note49
29Cardiotox
icity
:lower
incidencethan
5FU,mechanism
thou
ghtto
bedu
eto
coronary
vasospasm.Higherrisk
inpatientswith
cardiacor
renalcomorbidities.Bow
elperforation:
higher
incidencein
colon/rectalcancer
butcases
also
repo
rted
inbreastcancer
patients[57,
85,2
07]
30Incidenceof
hypersensitiv
ityreactio
nsincreaseswith
repeated
exposure.R
ateof
reactio
nsincreasedfrom
1%to27%
inwom
enwith
ovariancancerwho
received
>7cycles.D
esensitization
may
requ
ireICUadmission
[109
,142
]
206 M. J. Rivera et al.
31New
onseto
rworsening
HF,restrictivecardiomyopathy,pulm
onaryhypertension,m
yocardialischemia,and
infarctio
n,includingfatalities,may
occur.Patientswith
priorcardiovascular
diseaseor
advanced
age(>
75yearsof
age)
areatan
increasedrisk.A
cutekidney
injury
may
beassociated
with
progressivemyelomaalthough
prerenalinsults,tum
orlysis-lik
esyndrome,
ATN,and
TMAhave
occurred.A
cuteliv
erfailu
reandRPLShave
been
reported
rarely
with
carfilzom
ib.M
onito
rforheadache,seizure,lethargy,andhypertension.T
hrom
boem
bolism
and
hemorrhagerisksarethoughtto
beassociated
with
disease-relatedprocessesor
combinatio
nregimenscontaining
immunom
odulatoryagents.A
nticoagulatio
nor
antip
latelettherapy
isnot
requ
ired
forpatientsreceivingcarfilzom
ibmonotherapy.H
SV/VZVprophylaxisisrequired
during
therapydueto
risk
ofreactiv
ation[63,
178,25
0]32Black
boxwarning
fordose-related
pulm
onarytoxicity,especially
inpatientsreceiving>14
00mg/m
2cumulativedo
se.P
ulmon
aryfibrosismay
have
delayedon
set,occurringyearsafter
treatm
ent,especially
inchild
ren.
Other
risk
factors,asidefrom
cumulativedose,include
historyof
lung
diseaseandbaselin
eFVCor
DLCO<70
%[101,2
53]
33Sym
ptom
aticbradycardiacanoccur.Whentreatin
ghy
pertension,u
secautionwhenadministering
antih
ypertensiveagentsthatcancausebradycardia.Cases
ofgrade3and4pancreatitis
have
been
reported,including
fatalo
nes.Monito
ram
ylase/lip
aseatbaselin
e,periodically
during
therapyandwhenclinically
necessary[15,
167,
227]
34Cardiopulmon
aryarrestand/or
sudden
deathin
2–3%
ofpatientswith
squamouscellcarcinom
aof
thehead
andneck
treatedwith
cetuximab-based
therapy[69]
35Patientswith
ahistoryof
nephrotic
syndromeandreceivinghigh
pulsedosesof
chlorambucilare
atan
increasedrisk
ofseizures
[195,2
08]
36RPLShasbeen
repo
rted.Monito
rforheadache,seizure,
lethargy,andhy
pertension
.Renal
toxicity
isdo
se-related
andbecomes
moreprolon
gedandsevere
with
repeated
courses.
Hypocalcemiaandhypomagnesemia-related
tetany
have
been
reported.Incidence
ofhypersensitiv
ityreactio
nsincreaseswith
repeated
exposure,peaking
aftersixcycles.D
esensitizationmay
requ
ireICUadmission
[38,
229]
37Olderagemay
correlatewith
decreasedmetabolicclearanceof
clofarabineor
possiblydecreasednonrenalexcretionof
thedrug.C
lofarabine
may
causeacapillary
leak
syndromethatcanbe
preventedandmanaged
with
steroids.C
onsiderPJP
andfung
alprop
hylaxis.Serious
andfatalh
emorrhage,includingcerebral,G
I,andpu
lmon
aryhemorrhagehave
occurred
[77,
186]
38Riskof
GIperforation0.3%
.Medianfirsto
nsetof
LVEFdeclinewas
4months(23days
to13
months).R
habdom
yolysis:mediantim
eto
firsto
ccurrenceof
grade3or
4CPKelevations
16days
(12days
to11
mon
ths)[84]
39PJP
andno
ninfectio
uspn
eumonitishave
been
reported.PJP
prop
hylaxisis
recommendedin
patientswith
priorPJP
infectionor
lymphop
enia.Infusion-related
hyperglycemia
and
hypertension
have
also
occurred.S
erum
glucoselevelstypically
peak
at5–8hpo
stinfusion
,whereas
systolicanddiastolic
bloo
dpressure
peak
2hpo
stinfusion
[23]
40Sym
ptom
aticbradycardiacanoccur.Whentreatin
ghy
pertension
,use
cautionwhenadministering
with
antih
ypertensiveagentsthatcancausebradycardia.Pneum
onitison
setisgenerally
with
in3mon
thsof
treatm
entinitiatio
n.Severecasesof
liver
injury
have
been
repo
rted
during
thefirst6
weeks
oftherapy.Fatalcasesof
ketoacidosishave
been
reported
[190,2
03,2
23]
41Cardiotox
icity
isrelatedtoendothelialcapillarydamage.Riskisincreasedwith
high
erdo
ses,advanced
age,priorradiatio
ntothecardiacregion,and/orp
rior
useof
othercardiotoxicagents.
Reportedcardiotoxicitiesincludearrhythm
ias(atrialfi
brillation,atrialflutter,andventriculararrhythm
ias),H
F,heartblock,m
yocarditis(including
hemorrhagic),pericarditis,andpericardial
effusion
(including
cardiactamponade).Late-onsetpneumonitis(>
6mon
ths)
isassociated
with
increasedmortality.
Hyp
erhydrationplus/m
inus
MESNA
areutilizedto
help
prevent
hemorrhagiccystitisduring
theinfusion
ofcyclophosphamide.VODhasbeen
describedwith
high
dosesof
cyclophosphamidein
combinatio
nwith
otheragents,suchas
TBIor
busulfan
aspartof
aconditioningregimen
forstem
celltransplant
[21,
62]
42Doses
�3g/m
2every12
hhave
been
repo
rted
tocausean
acutecerebellarsyn
drom
ein10–25%
ofpatients.Patients>40
yearsof
agewho
have
abno
rmalliv
eror
renalfun
ction,un
derlying
neurologicdy
sfun
ction,
orwho
receiveatotald
oseof
>30
g,areparticularly
vulnerableto
developing
cerebellartoxicity
[19,
102,
118,
226]
43Medianonsetof
cardiomyopathyis
4monthswhenused
aloneor
8monthsifused
concurrently
with
tram
etinib.Fever
iscommon
with
dabrafenib
andtram
etinib
andcanlead
tohy
potension,
dizziness,andkidn
eydy
sfun
ctionifdehydrationoccurs[171,2
55]
44Hepatotoxicity
may
beaccompanied
byhepatic
vein
thrombosisandhepatocellu
larnecrosis[11]
45Increasedrisk
ofVODin
child
ren<4yearsof
age[182]
46Infusion-related
reactio
nsincludingbronchospasm
,pneum
onitis,andpulm
onaryedem
amay
occur.Com
binatio
nregimenswith
corticosteroidsandprem
edicationwith
antih
istamines
and
antip
yreticshave
helped
alleviatesymptom
s,although
patientsmay
still
beatrisk
ford
elayed
infusion
reactio
ns.C
onsiderb
roncho
dilatorsinpatientswith
ahistoryof
COPDor
FEV1<80
%.
HSVprophylaxisshouldstartw
ithin1weekof
initiationandcontinue
for3
monthsfollo
wingtreatm
ent.May
resultinafalse-positiv
eIndirectCoombs
testthatmay
persistfor
upto6mon
ths
afterthelastinfusion
[111]
47Optim
izeserum
potassium
andmagnesium
levelspriorto
anddu
ring
therapyto
redu
cerisk
ofcardiotoxicity.Pleural
effusionscanoccur.Managem
entof
pleuraleffusionsconsistsof
temporary
dose
interruptio
n,dose
reductions,diuretics,and/or
corticosteroids.Pulmonaryarterialhypertension
typically
occursafter8–
48monthsof
exposure.Increased
risk
ofbleeding
inthosewith
advanced
diseaseandthrombocytopenia[28,
39,5
5,13
4,15
2,19
4,22
0]48Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinalradiationtherapy,andconcom
itantadministrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelortrastuzum
ab.T
heincidenceof
cardiactoxicityincreasesaftera
total
cumulativedo
seexceeding40
0–55
0mg/m
2in
adults,3
00mg/m
2in
child
renmorethan
2yearsof
age,or
10mg/kg
inchild
renless
than
2yearsof
age[27]
49Cardiotox
icity
may
occurdu
etotheanthracyclinecompo
nent(daunorubicin)
oftheform
ulation.Observe
thesamerisk
factorsforcardiotoxicity
aswith
conventio
nalanthracyclin
es.T
his
form
ulationisnotinterchangeablewith
otherform
ulations
ofdaunorubicin
andcytarabine
[114,1
32]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 207
Tab
le1D
Neuro
Cardiac
Pulmon
ary
Renal
GI
End
ocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
Pericardialeffusions
Severehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Dinutuxim
abX
XX
XX
XSee
Note50
Docetaxel
XX
XX
XX
XX
XSee
Note51
Dox
orub
icin
XX
XSee
Note52
Doxorubicin
liposom
alX
XX
See
Note53
Durvalumab
XX
XX
XX
XX
XX
XSee
Note54
Enasidenib
XSee
Note55
Epirubicin
XSee
Note56
Erlotinib
XX
XX
XX
See
Note57
Etopo
side
XX
XX
See
Note58
Everolim
usX
XX
XX
XX
XSee
Note59
Fludarabine
XX
XX
See
Note60
Gefitin
ibX
XX
XSee
Note61
Gem
citabine
XX
XX
XX
XSee
Note62
Gem
tuzumab
ozogam
icin
XX
XSee
Note63
Ibritumom
abX
See
Note64
Ibrutin
ibX
XX
XSee
Note65
Idarubicin
XSee
Note66
Idelalisib
XX
XX
XX
See
Note67
50Can
causecapillary
leak
syndromewith
hypotension,severehypokalemiaandhyponatrem
ia,H
US,and
subsequentrenalfailure.R
PLScanoccur–
mon
itorfor
headache,seizure,lethargy,
andhy
pertension
[245
]51Fluid
retention,
dueto
capillary
leakage,canlead
tonon-cardiogenicpulm
onaryedem
aor
pleuraleffusions.D
iureticsrecommendedfortreatm
ent[16
2,19
9,21
2]52Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinal
radiationtherapy,
andconcom
itant
administrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelor
trastuzumab.Riskof
cardiomyopathyis
proportio
nalto
the
cumulativeexposure
with
incidences
from
1%to
20%
forcumulativedosesof
300mg/m
2–500
mg/m
2.A
tacumulativedo
seof
400mg/m
2,the
risk
ofdeveloping
HFis5%
[26,
258]
208 M. J. Rivera et al.
53Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinalradiationtherapy,andconcom
itant
administrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelo
rtrastuzumab.R
iskof
cardiactoxicity
hasbeen
repo
rted
tobe
11%
with
cumulativedosesbetween450and550mg/m
2[113]
54May
causesevere
immune-mediatedadverseeventsincludingpneumonitis,medianonset1.8months;hepatitis,medianonset~5
2days
(2–45weeks);andim
mune-mediatedthyroid
disorders,medianon
set3mon
ths(range:2weeks
to13
mon
ths).May
aggravateun
derlying
autoim
munedisorders.Managem
entincludes
holdingtherapy,system
iccorticosteroids,+/�
additio
nalimmun
osuppressants(e.g.,inflixim
ab,m
ycophenolateandvedolizum
ab).ConsiderPJP
prophylaxisin
patientswith
prolongedcorticosteroid
exposure
[12,
33]
55Differentiatio
nsyndromeiscommonlyassociated
with
thedevelopm
entofh
yperleukocytosis,pulmonaryedem
a,generalized
edem
a,headache,bonepain,and
renalfailure,w
ithamedian
onsetof48
days
(10–34
0days).Managem
entincludessteroids
and/or
discon
tinuatio
nof
enasidenib
depend
ingon
severity.F
ormanagem
ent,please
refertothepackageinsert.P
atientswith
leukocytosiscanbe
managed
with
hydrox
yurea[230]
56Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinal
radiationtherapy,
andconcom
itant
administrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelor
trastuzumab.Riskof
cardiomyopathyis
proportio
nalto
the
cumulativeexposure
with
incidences
from
0.9%
to3.3%
forcumulativedosesfrom
550mg/m
2–900
mg/m
2[144]
57The
risk
ofCVAisincreasedin
patientswith
pancreaticcancer,w
ithahigherincidencefoundin
thosereceivingerlotin
ib+gemcitabine
(2.5%)versus
gemcitabine
alon
e.Medianon
seto
fILDsymptom
sis39
days
(5days
tomorethan
9months)afterinitiatingtherapy.Renalfailu
remay
arisefrom
exacerbatio
nof
underlying
baselin
ehepatic
impairmentorseveredehydration.
Rareincidenceof
renalfailure
inmonotherapy
(0.5%)and1.4%
whencombinedwith
gemcitabine
[79,
180]
58[2,2
02]
59Non
infectious
pneumon
itis,
PJP,andinvasive
fung
alandviralinfections
have
been
reported.Adm
inisterprophy
laxisforPJP
whenconcom
itant
useof
corticosteroidsor
other
immunosuppressive
agentsarerequ
ired
[120
,164]
60Incidenceof
pulm
onarytoxicity
8.6%
,morelik
elywith
CLL.Pneum
onitisoccurs
days
toweeks
aftertherapyandmay
occurfollo
wingthefirstcycle;
managem
entincludes
system
iccorticosteroids.Fludarabine
canalso
causeautoim
munehemolyticanem
ia(A
IHA).Serious
andsometim
esfatalinfectio
nsincludingopportunistic
andreactiv
ationof
latent
viralinfectio
nssuch
asVZV,E
BV,and
JCvirushave
been
repo
rted
[100
,231,2
46]
61Medianon
seto
fILDsymptom
s3–6weeks,w
ithfatalitiesreported.S
erum
hepatic
enzymeelevations
typically
occurafter4–
12weeks
oftreatm
entw
ithahepatocellu
larpattern
[17]
62Associatedwith
arangeof
pulm
onarytoxicities:interstitialpneum
onitis,capillary
leak,non
-cardiog
enicpu
lmon
aryedem
a,andpu
lmon
aryfibrosis;onsetcanbe
upto2weeks
follo
wingthe
lastdose.P
otentialfor
radiationrecall.HUShasbeen
reported,including
fatalitiesor
need
ford
ialysisduetorenalfailure.C
apillaryleak
syndromeandRPLShave
been
repo
rted
[46,72,206,
244]
63Optim
izepotassiumandmagnesium
priortoandduring
therapytoreduce
risk
ofcardiotoxicity.Increased
risk
forV
OD.M
edianonsetofh
yperbilirubinem
iaandincreasesinASTandALT
8days
andmedianduratio
n20
days
follo
winginitiationof
therapy[145,2
24,2
49]
64SJS
may
occurwith
indays
to4mon
thsfollo
winginfusion
[117]
65Arrhythmias(i.e.,ventriculararrhythm
ias,
atrial
fibrillation,
andflutter)
have
occurred,particularly
inpatientswith
cardiacrisk
factors,
hypertension,acuteinfections,or
historyof
arrhythm
ias.Cases
ofPJP
have
been
repo
rted
with
amedianon
seto
f6mon
ths(2–2
4months).Invasivefungalinfections
(i.e.,aspergillosis,cryptococcal,andmucor)have
been
reported.
Con
siderPJP
andfung
alprophy
laxisin
patientswith
lymphop
eniaor
prolon
gedcorticosteroid
expo
sure.M
ajor
hemorrhage(grade
3–4)
hasbeen
reported
with
BTKinhibitors.C
onsider
with
holdingfor3–7days
priorto
procedures
dependingon
therisk
ofbleeding
[3,2
0,14
6,17
6,19
3,21
9]66Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinalradiationtherapy,andconcom
itant
administrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelo
rtrastuzumab.E
stim
ated
incidenceof
heartfailu
reis5–18
%with
doses>90
mg/m
2[258]
67Pneum
onitisandorganizing
pneumoniamay
occur1-15
monthsafterinitiationof
idelalisib
andshould
bemanaged
with
corticosteroids.GIperforationtypically
preceded
bymoderateto
severediarrhea.M
edianon
setofd
iarrhea1.9mon
ths(range,0.0–2
9.8mon
ths).A
nti-motilitydrugssuch
asloperamideareno
tusefulinthemanagem
entofidelalisib-ind
uced
diarrhea,w
hich
isbestmanaged
with
dose
interruptio
ns;the
mediantim
eto
resolutio
nof
diarrhea
canbe
upto
1month.E
ntericbudesonide
orsystem
iccorticosteroidsmay
beconsidered
fortreatm
ento
fsevere
orunresolved
diarrhea,leading
toshortertim
eto
resolutio
ncomparedto
interruptio
nalone(1–2
weeks
vs.1
month).Elevatio
nsin
ALT
orAST>5tim
esULNhave
been
observed,
usually
occurringwith
inthefirst1
2weeks
oftreatm
ent.Mosttransam
inaseelevations
werereversiblewith
dose
interruptio
n.Mediantim
eto
PJP
event4
.5monthsafterinitiation.Consider
PJP
prop
hylaxisandCMVmon
itoring
[93]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 209
Tab
le1E
Neuro
Cardiac
Pulmon
ary
Renal
GI
End
ocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
PericardialeffusionsSeverehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Ifosfamide
XX
XX
XX
XX
XSee
Note68
Imatinib
XX
XX
XX
See
Note69
Inotuzum
abozogam
icin
XSee
Note70
Ipilimum
abX
XX
XX
XX
XX
XX
XSee
Note71
Irinotecan
XX
XX
XSee
Note72
Ixabepilo
neX
XSee
Note73
L-A
sparaginase
XX
XX
XSee
Note74
Lapatinib
XX
XX
XX
See
Note75
Lenalidom
ide
XX
XX
XSee
Note76
Lenvatin
ibX
XX
XX
XX
XX
XX
See
Note77
Lisocabtagene
maraleucel
XX
XX
XX
XX
XSee
Note78
Mechlorethamine
XSee
Note79
Melph
alan
XX
XSee
Note80
Metho
trexate
XX
XX
XX
XX
See
Note81
Midostaurin
XX
See
Note82
Mito
mycin-C
XX
See
Note83
Mito
xantrone
XSee
Note84
Nab-paclitaxel
XX
See
Note85
Necitu
mum
abX
XSee
Note86
Nelarabine
XX
See
Note87
68Ifosfamideencephalopathy
(ranging
from
mild
somnolenceto
confusionandhallu
cinatio
nsto
coma)
may
occurwith
inhoursto
days
afteradose.R
iskfactorsforCNStoxicity
include
hypoalbuminem
ia,p
re-existingrenaldysfunction,
concom
itant
useof
aprepitant,and
priorcisplatin
exposure.IValbumin
andthiaminesupplementatio
narerecommendedforpreventio
n.Encephalopathytypically
resolves
with
in2–3days
afterdiscontin
uatio
n;however,IVmethylene
blue
may
beconsidered
asatreatm
entoptio
n.Cardiotoxicity
includingarrhythm
ias(i.e.,
SVT,atrialfibrillation,andpulselessventriculartachycardia),heartfailurewith
congestio
nandhypotension,pericardialeffusion,fibrinouspericarditis,andepicardialfibrosismay
occur.VOD
hasbeen
repo
rted
incombinatio
nregimens[22,
183]
210 M. J. Rivera et al.
69Heartfailu
rehasbeen
reported,alth
ough
mostly
inthosewith
othercom
orbiditiesandrisk
factors,includ
ingadvanced
ageandprevious
cardiacdisease.Alth
ough
rare,itisworthno
tingthe
repo
rtsof
interstitialpneum
onia.M
edianon
set7
weeks
(1.5–40weeks)andpresentatio
ninclud
eslow-grade
fever,drycoug
h,andprogressivedy
spneaon
exertio
n,with
orwith
outhyp
oxia.
Managem
entincludessteroids
and/or
drug
discontin
uatio
nof
imatinib
[175
]70VODcanoccurdu
ring
oraftertreatm
ent.Medianon
seto
fVODwas
15days
(range,3
–57days)forpatientsreceivingstem
celltransplant
[123,1
24]
71Pneum
onitis:highestincidence
whengivenwith
nivolumab
(5–10%
incidence)with
medianonsetofsymptom
s2.6monthsfollo
wingtherapyinitiation.Onsetof
GIsym
ptom
sistypically
6weeks
ormoreafterinitiatingtherapy.Moderateto
severe
endocrinedisorders:medianonset2.2–2.5mon
ths.Im
mun
e-mediatedhepatitis(grade
3or
4):medianon
set2mon
ths.Treat
toxicitiesby
holdingipilimum
abandadministering
corticosteroids.ConsiderP
JPandfungalprophylaxisinpatientswith
prolongedcorticosteroidexpo
sure.A
lthough
rare,lethalm
yocarditis
accompanied
bymyositis
inpatientstreatedwith
acombinatio
nof
nivolumab
andipilimum
abhasbeen
reported
[34,
40,4
2]72Pulmonarytoxicity
morecommon
with
irinotecan
than
topotecan.
Higherrisk
inpatientswith
pre-existin
glung
disease,priorthoracicradiation,
useof
pneumotox
icdrugs,andcolony
-stim
ulatingfactors.Severe/fataldiarrhea
canoccurwith
irinotecan.E
arly
diarrhea
(with
in24
hrs)isaccompanied
byanticholin
ergicsymptom
s.Latediarrhea
canoccurmorethan
24hrs
follo
wingdo
seadministration.
Cases
ofmegacolon
andbo
welperforationhave
been
repo
rted
[192
]73MIandventriculardysfunctionhave
been
reported
[35]
74Noted
complications
typically
occurafterseveralweeks
oftreatm
entandoftendu
ring
theindu
ctionph
ase.
Encephalopathymay
berelatedto
hyperammonem
iaandRPLS.Serious
thrombo
ticevents,including
sagittalsinus
thrombo
sis,have
been
repo
rted
[5,7
8,99
,126]
75Decreases
inLV
EFhave
been
reported,usually
with
inthefirst3
mon
thsof
treatm
ent.Optim
izeserum
potassium
andmagnesium
levelspriorto
anddu
ring
therapy.Caserepo
rtsdescribe
seriousor
fatalh
epatotoxicity,u
sually
1–3mon
thsfollo
wingtreatm
entinitiatio
n[165,1
84,1
85]
76Throm
boprop
hylaxiswith
either
aspirinor
aLMWHshould
beconsidered
forpatientsreceivinglenalid
omidein
combinatio
nwith
chem
otherapy
and/or
dexamethasone
[140,2
41]
77RPLShasbeen
reported.M
onito
rforheadache,seizure,lethargy,andhypertension.M
ediantim
eto
onsetof
newor
worsening
hypertension
is16
–35days.C
anim
pairwound
healing;
should
beheld
atleast6
days
priorto
surgicalprocedures
[67]
78Lisocabtagene
maraleucelisaCART-celltherapyundergoing
FDAapproval.L
atestavailabledatarevealed
a1%
incidenceof
severe
CRS(35%
anygradeCRS)and12
%incidenceof
severeICANS(19%
anygradeICANS).Managem
entofC
RSand/or
ICANSisgradingdependentbutmay
includesupportiv
ecare,tocilizumab,and/orsystemiccorticosteroids.Anti-seizure,
PJP,and
HSVprophylaxissimilarto
otherCART-celltherapiesshould
beconsidered
[119]
79PJP
andCMVpn
eumoniahave
occurred
dueto
severe
andprolon
gedneutropenia.Con
siderPJP
prophy
laxisandCMVmon
itoring
[43]
80GItoxicity,including
grade3/4mucositis,hasbeen
reported
with
high-dosemelphalan.C
ryotherapy
may
help
prevent/reducemucositisseverity
[95]
81Glucarpidasemay
beconsidered
forpatientsreceivinghigh-dosemethotrexate(H
DMTX)with
delayedclearance(serum
methotrexatelevels>
1μm
ol/L
beyond
42hafterthestartof
HDMTXinfusion)andrenald
ysfunctio
n(serum
creatin
ine>1.3mg/dL
or>50%
increase
from
baselin
e).L
eucovorincalciumshould
notb
eadministeredwith
in2hof
glucarpidase
dueto
competin
gbindingsites.Intrathecalm
ethotrexateiscommonly
associated
with
aseptic
meningitis
characterizedby
fever,headache,and
vomiting
thatcanlastseverald
ays.Generalized
and
focalseizures
have
been
reported.Methotrexatemay
increase
therisk
ofdeveloping
life-threateningopportunistic
infections.Donotinitiatepenicillins,fluo
roqu
inolon
es,sulfonam
ide
antib
iotics,nonsteroidalanti-inflam
matorydrugs,or
proton
pumpinhibitorsuntil
methotrexatehascleared[80,
129]
82Fataleventsinvo
lvingpu
lmon
arytoxicity
have
occurred
[232]
83Infrequent
butseverepulm
onarytoxicity
(e.g.,ARDS)hasbeen
reported.H
USandsubsequent
renalfailurehave
been
reported.D
ose-relatedpulm
onarytoxicity
(>20
mg/m
2)[138
,177,
234,
248]
84Onsetof
cardiotoxiceffectsof
anthracyclines
canoccurdu
ring
orim
mediately
afterinfusion
(acuteon
set),w
ithin
1year
ofexposure
(early
onset),and
from
1–20
years(lateon
set)after
initial
expo
sure.Factors
increasing
therisk
ofcardiactoxicity
includetheextent
ofanthracyclineexposure,high
erdo
ses,olderage,
pre-existin
gcardiacdisease,
concurrent
orprevious
mediastinalradiationtherapy,andconcom
itantadministrationof
cardiotoxicchem
otherapy
regimenssuch
aspaclitaxelortrastuzum
ab.E
stim
ated
risk
ofCHFis2.6%
ford
oses
upto14
0mg/
m2[74]
85[1]
86Cardiopulmonaryarrestand/or
sudden
deathhasbeen
reported
inpatientstreatedwith
necitumum
abincombinatio
nwith
gemcitabine
andcisplatin
.Severehy
pomagnesemiaiscommon
inthosetreatedwith
necitumum
ab,gem
citabine,and
cisplatin
,with
amedianonseto
f6weeks.O
ptim
izeserum
potassium,m
agnesium
,and
calcium
during
andforatleast8
weeks
follo
wing
administration.
Cerebralstrok
eandMIhave
also
been
repo
rted
[68,
240]
87Mostneurologictoxicitiesoccurw
ithin12
days
ofinfusion
oraftersuccessivecycles
oftherapy.The
mostcom
mon
grade3/4neurologicadverseeventsreported
includeconfusion,malaise,
somnolence,ataxia,m
uscleweakness,andperipheralneuropathies
[121
,130]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 211
Tab
le1F
Neuro
Cardiac
Pulmon
ary
Renal
GI
Endocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
Pericardialeffusions
Severehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Nilo
tinib
XX
XX
XX
XX
XSee
Note88
Niraparib
XSee
Note89
Nivolum
abX
XX
XX
XX
XX
XX
XSee
Note90
Obinu
tuzumab
XX
See
Note91
Ofatumum
abX
XSee
Note92
Olaparib
XX
XSee
Note93
Osimertin
ibX
XX
See
Note94
Oxalip
latin
XX
XX
XX
XX
XSee
Note95
Paclitaxel
XX
XSee
Note96
Palbo
ciclib
XSee
Note97
Panitu
mum
abX
XX
See
Note98
Panob
inostat
XX
See
Note99
Pazopanib
XX
XX
XX
XX
XX
XSee
Note10
0
PEG-asparaginase
XX
XX
XSee
Note101
Pem
brolizum
abX
XX
XX
XX
XX
XX
XSee
Note102
Pem
etrexed
XX
XSee
Note103
Pentostatin
XX
XSee
Note10
4Pertuzumab
XX
See
Note10
5
Pom
alidom
ide
XX
XX
XSee
Note10
6Pon
atinib
XX
XX
XX
XX
XSee
Note10
7
Pralatrexate
XX
See
Note10
888Riskof
QTprolongatio
nwarrantsabaselin
e12-leadEKG
with
repeat
assessmentafter7days
oftherapy,follo
winganydose
change,andregularlyduring
treatm
ent.Optim
izeserum
potassium
andmagnesium
levelspriorto
anddu
ring
therapy.Biochem
icalabnorm
alities
arecommon
(i.e.,increasedlip
ase,glucose,totalb
ilirubin,
ALT
)[4,9
4,10
3,13
5,17
2,19
8]89Hypertensivecrisishasbeen
reported
[237]
90May
causesevere
immune-mediatedadverseeventsincludingpneumonitis,medianonset1.6–3.5months(1
dayto
22.3
months);nephritis,2.7–4.6mon
ths(9
days
to12
.3mon
ths);
hepatitis,2
.1–3
.3months(6
days
to11
months);colitis,1
.6–5.3
mon
ths(2
days
to21
mon
ths);adrenalinsufficiency
(acrossseveralclinicaltrials),3–4.3mon
ths(15days
to21
mon
ths);
212 M. J. Rivera et al.
hyperthyroidism,23days
to1.5mon
ths(1dayto14
.2mon
ths);hyp
othy
roidism,2–3
mon
ths(1
dayto16
.6mon
ths);and
hypoph
ysitis,4.9mon
ths(1.4–11mon
ths).M
ayaggravateun
derlying
autoim
munedisorders.
Managem
entincludes
holdingtherapy,
system
iccorticosteroids,
and+/�
additio
nalim
munosup
pressants(e.g.,inflixim
ab,mycophenolate,andvedolizum
ab).
Con
siderP
JPprop
hylaxisinpatientswith
prolon
gedcorticosteroidexposure.A
lthough
rare,lethalm
yocarditisaccompanied
bymyo
sitis
inpatientstreatedwith
acombinatio
nof
nivolumab
andipilimum
abhasbeen
reported
[33,
36,116,1
33,1
59,1
60]
91HBVreactiv
ationmay
occurduring
andup
to24
monthsafterdiscontin
uatio
nof
anti-CD20
antib
odies.Patientson
antiv
iralprophylaxisshouldcontinue
for6–12
monthsaftercompleting
treatm
ent.JC
virusinfectionresulting
inPMLhasbeen
reported
[32,
106]
92HBVreactiv
ationmay
occurduring
andup
to24
monthsafterdiscontin
uatio
nof
anti-CD20
antib
odies.Patientson
antiv
iralprophylaxisshouldcontinue
for6–12
monthsaftercompleting
treatm
ent.Fatalcasesof
PMLhave
been
repo
rted
[32,
106]
93[14,
64]
94[18]
95Ventricular
arrhythm
ias,includingfatalT
orsadesde
Pointes,h
avebeen
reported.O
ptim
izepotassium
andmagnesium
priorto
andduring
therapy.Cases
ofpu
lmon
aryfibrosis,including
fatalevents,have
been
reported.R
PLShasbeen
repo
rted.M
onito
rforheadache,seizure,lethargy,andhy
pertension
[154,2
04,2
11,2
22]
96[29,
162]
97[191]
98Monito
rforhypomagnesemiaandhypocalcem
iapriorto,duringandup
to8weeks
aftertherapy.Severederm
atologiccomplications
may
effectup
to15%
ofpatientsandcanlead
tolife-
threateninginfectious
complications
such
asnecrotizingfasciitisandabscesses[8,1
79]
99QTprolongatio
nisaclasseffectof
HDACinhibitors,alth
ough
theincidencemay
belower
than
initially
reported.O
ptim
izeserum
potassium
andmagnesium
levelspriorto
anddu
ring
therapy[173,2
05]
100RPLSisrarebu
tserious.M
onito
rfor
headache,seizure,lethargy,andhy
pertension
.Som
efatalcases
ofhepatotoxicityhave
been
repo
rted.Serum
hepatic
enzymeelevations
generally
occur
with
in4–12
weeks.The
mostcommon
hemorrhagic
eventswerehematuria
(4%),epistaxis(2%),hemoptysis(2%),andrectal
hemorrhage.
Rarecasesof
hypertensive
crisishave
been
repo
rted,m
ostcases
ofhy
pertension
with
infirst1
8weeks
oftherapy.TMAincludingTTPandHUScanoccur,generally
with
in3mon
thsof
treatm
entinitiatio
n[136,1
58,1
66,2
09]
101Com
plications
typically
occurafterseveralweeks
oftreatm
entduring
theinductionphase.Clin
ical
symptom
ssuggestiv
eof
pancreatitishave
been
reported
tooccurwith
in15
days
oftreatm
ent[65]
102May
causesevere
immune-mediatedadverseeventsincludingpn
eumonitismedianon
set3
.3mon
ths(2
days
to~1
9mon
ths)andismorecommon
with
priorthoracicradiation,
hepatitis
1.3mon
ths(8
days
to21
.4mon
ths),colitis
3.5mon
ths(10days
to16
.2mon
ths),autoim
mun
eneph
ritis
5.1mon
ths(12days
to12
.8mon
ths),hy
perthyroidism
1.4mon
ths(1
dayto
~22mon
ths),and
hypo
thyroidism
3.5mon
ths(1
dayto
19mon
ths).M
ayaggravateun
derlying
autoim
mun
edisorders.Managem
entincludesho
ldingtherapy,system
iccorticosteroids,and
+/�
additio
nalimmunosuppressants(e.g.,inflixim
ab,m
ycop
heno
late,and
vedolizum
ab).ConsiderPJP
prop
hylaxisin
patientswith
prolon
gedcorticosteroid
exposure
[33,
148,
159,
160]
103Proph
ylactic
folic
acid
andvitamin
B12
supplementatio
nshould
beprov
ided
whilereceivingpemetrexedto
redu
cetherisk
ofhematolog
ictoxicity.R
enaldamagerang
esfrom
acuteto
chronickidn
eyinjury
dueto
tubu
larandinterstitiald
amage[70,
252]
104ConsiderHSV/VZVprop
hylaxis[105
,142]
105Prior
anthracyclinetherapyor
chestirradiatio
nmay
increase
therisk
forcardiotoxicity
(riskislower
than
thatseen
with
trastuzumab)[83,
235]
106Throm
boprop
hylaxiswith
either
aspirinor
aLMWHshou
ldbe
considered
forpatientsreceivingpo
malidom
idein
combinatio
nwith
chem
otherapy
and/or
dexamethasone
[49,
92].
107Vigilant
monito
ring
forvascular
eventsisrecommended(i.e.,MI,stroke,stenosisof
largearterialvesselsof
thebrain,
severe
peripheralvascular
disease).V
ascularocclusion/eventscan
occurwith
inweeks
ofstartin
gtherapyandisnotd
osedependentand
requires
interruptio
nor
perm
anentd
iscontinuatio
nof
therapy.Arrhythmias,such
asatrialfibrillationandsymptom
atic
bradycardia,have
been
reported.H
ypertensioncanbe
severeandshouldbe
managed
asclinicallyindicated.Hepatotoxicity
:medianonset3
months(range,lessthan
1mon
thto47
mon
ths);
may
requiretreatm
entinterruptionor
discontin
uatio
n.Bleedingcanoccurd
uringtherapy,particularlyinpatientswith
acceleratedor
blastphase
diseaseandthrombocytopenia.RPLShasbeen
repo
rted.M
onito
rforheadache,seizure,lethargy,andhy
pertension
[53,
54,1
39,1
55,2
47]
108Prophylactic
folic
acid
andvitamin
B12
supplementatio
narenecessaryto
reduce
hematologictoxicity
[6]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 213
Tab
le1G
Neuro
Cardiac
Pulmon
ary
Renal
GI
Endocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
PericardialeffusionsSeverehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
Pleuraleffusions
Organizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Ram
ucirum
abX
XX
XX
XSee
Note10
9
Regorafenib
XX
XX
XX
XSee
Note110
Ribociclib
XX
XSee
Note111
Ritu
ximab
XX
XSee
Note112
Rom
idepsin
XX
XSee
Note113
Ruxolitinib
XSee
Note114
Sipuleucel-T
XX
See
Note115
Son
idegib
XX
XSee
Note116
Sorafenib
XX
XX
XX
XX
XX
XX
See
Note117
Sun
itinib
XX
XX
XX
XX
XX
See
Note118
Temozolom
ide
XX
See
Note119
Thalid
omide
XX
XX
XX
See
Note12
0Thiotepa
XX
XSee
Note12
1
Tisagenlecleucel
XX
XX
XX
XX
XSee
Note12
2To
potecan
XX
See
Note12
3
Trabectiden
XX
XX
XSee
Note124
Trametinib
XX
XX
XX
XX
XSee
Note125
Trastuzum
abX
XX
XX
See
Note12
6
Tretin
oin(all-transretin
oicacid)
XX
XX
XX
See
Note127
109Serious,sometim
esfatal,MI,cardiacarrest,andCVA
eventshave
occurred
inclinical
trials.Can
impairwound
healing;
therapyshould
beheld
priorto
surgical
procedures.Rates
ofhemorrhageor
GIperforationunknow
ninpatientson
chronicNSAID
sor
anticoagulatio
nas
manystudiesexcluded
thesepatients;therefore,usecautiouslyincombinatio
nwith
theseagents
[10,
71]
110Can
impairwou
ndhealing.
Discontinue
2weeks
priorto
surgicalprocedures
andresumeon
cewou
ndhashealed.R
PLShasbeen
reported.M
onito
rforheadache,seizure,lethargy,and
hypertension
[25,
158]
111Mon
itorand
optim
izeserumpo
tassium,calcium
,pho
spho
rus,andmagnesium
beforeanddu
ring
therapyas
electrolyteim
balances
may
occurtoredu
cerisk
ofcardiotoxicity.M
edianon
set
ofgrade3or
high
ertransaminaseelevations
~2mon
ths,with
mediantim
eto
resolutio
nto
grade2or
lower
of24
days
[104,1
69]
214 M. J. Rivera et al.
112Abd
ominalpain,bow
elob
struction,andperforationhave
been
repo
rted,w
ithan
averageon
seto
fsymptom
s~6
days
(1–77days).JC
virusinfectionresulting
inPMLhasbeen
reported.
Mediantim
etoPMLdiagnosis16
monthsfollo
wingrituximab
initiationandmediantim
efrom
lastrituximab
dose
5.5months.HBVreactiv
ationmay
occurd
uringandup
to24
mon
thsafter
discon
tinuatio
nof
anti-CD20
antib
odies.Patientson
antiv
iralprophy
laxisshould
continue
for6–12
monthsaftercompletingtreatm
ent[32,4
7,10
6]113QTprolongatio
nisaclasseffectof
HDACinhibitors,alth
ough
theincidencemay
belowerthan
initiallyreported.O
ptim
izeserumpotassium,m
agnesium
,and
calciumlevelspriorto
and
during
therapy.Viralreactiv
ationhasoccurred
during
andwith
in30
days
ofinitiation.
Considerantiv
iralprophylaxisforpatientswith
historyof
EBVor
HBV[50,
205]
114Bacterial,mycob
acterial,fungal,andviralinfections
have
occurred
includ
ingTB,PML,HSV/VZV
andincreasedHBV
viralload.With
draw
alsyndromecanoccurwith
abrupt
discontin
uatio
nof
treatm
entand
ischaracterizedby
acuterelapseof
diseasesymptom
ssuch
asacceleratedsplenomegaly,worsening
cytopenias,and
sepsis-likesyndrome.Itcanbe
managed
with
corticosteroidswith
aslow
taperoff[108]
115Vasculardisordersinclud
ingMIandstroke
have
been
reported.A
cuteinfusion
reactio
nswith
in1dayof
infusion
have
been
reported
[61].
116CPKelevations
>grade2occuratamedianof
13weeks.C
PKlevelsshou
ldbe
mon
itoredatbaselin
eandperiod
ically
during
therapy.Rarecasesof
rhabdo
myo
lysishave
been
reported
[110,2
33]
117HF,myo
cardialischemia,and
/orMIhave
been
repo
rted.A
cuteliv
erinjury
generally
occursafewdays
toup
to8weeks
aftertreatm
entinitiatio
n.Possibleim
paired
wound
healing.RPLS
canrarely
occur.Mon
itorforheadache,seizure,lethargy,andhy
pertension
[24,
216]
118RPLScanrarely
occur.Caserepo
rtshave
occurred
1–34
weeks
follo
wingtreatm
entinitiation.
Monito
rforheadache,seizure,
lethargy,andhy
pertension.Cardiac
events
includ
ing
myocardialischemia,M
I,reductions
inLV
EF,andcardiacfailu
reincludingdeathhave
occurred
[56,
156,
158,18
9]119PJP
prophylaxisisrecommended[147]
120VTE,including
ischem
icheartd
isease,M
I,andCVAhave
occurred
inpatientsreceivingthalidom
ideanddexamethasone.T
hrom
boprophylaxiswith
eitheraspirinor
aLMWHshould
beconsidered
forpatientsreceivingthalidom
idein
combinatio
nwith
chem
otherapy
and/or
dexamethasone.S
eizuresandbradycardiahave
been
repo
rted
inpostmarketin
gdata[51]
121Parentdrugand/or
metabolitesmay
bepartially
excreted
throug
htheskin;severeblistering
anddesquamationcanoccur.Asaresult,
patientsshouldshow
er/bathe
atleasttwicedaily
while
receivingtreatm
entand
during
the48
hfollo
wingtherapy.Hepatotoxicity
referstoVOD,w
hich
hasbeen
reported
whenhigh
dosesareused
incombinatio
nwith
otherchemotherapy
aspartof
aconditioningregimen
forstem
celltransplant
[58,
257]
122CRS:M
edianon
set3
days
(1–22days);mediandu
ratio
n8days
(1–3
6days).Monito
rforsign
sor
symptom
sof
CRSforatleast4
weeks
aftertreatm
ent.Key
manifestatio
nsinclud
ehigh
fever,hy
potension,
andshortnessof
breath
andmay
beassociated
with
hepatic,renal,and
cardiacdy
sfun
ctionandcoagulopathy.R
iskfactorsforsevere
CRSarehigh
pre-infusion
tumor
burden
(>50%
blastsin
bone
marrow),uncontrolledor
acceleratin
gtumor
burden
follo
winglymphodepletin
gchem
otherapy
(fludarabineandcyclophosphamide),activeinfections,and/or
inflam
matoryprocesses
ICANS:Mostneurolog
icaltoxicitiesoccurred
with
in8weeks
andgenerally
resolved
with
in12
days.M
ostcommon
neurologicaltoxicitiesincludeheadache,encephalopathy,delirium,
anxiety,andtrem
or.F
atalandseriouscasesof
cerebraledem
ahave
occurred;o
ther
seriouseventsincluded
leukoencephalopathyandseizures.
Managem
ento
fCRSwith
orwith
outICANSdependson
gradingor
severity
butincludessupportiv
ecare,tocilizumab,and/orsystem
iccorticosteroids.Grade
2or
high
erICANSwith
out
CRSshould
betreatedwith
corticosteroidsaloneas
thereisinsufficientdata
with
tocilizum
abin
thissetting.Other
interleukinantagonists(e.g.,siltu
ximab)andanti-Tcelltherapiesare
currently
beingevaluated.
Hyp
ogam
maglobu
linem
iasecondarytoB-cellaplasiamay
persistfor
upto13
mon
thsandincrease
therisk
forinfectio
ns.PJP
andHSVprophy
laxisarerecommendedforatleast1yearafter
CAR-T
celltherapy[143,1
74]
123Post-marketin
gcasesof
ILD
have
been
reported.Higherrisk
inpatientswith
baselin
einterstitiallung
disease,
pulm
onaryfibrosis,lung
cancer,thoracic
exposure
toradiation,
useof
pneumotoxicdrugs,and/or
colony-stim
ulatingfactors[168
]124Grade
3or
4CPKelevations
have
been
reported
with
amedianonsetof
2monthsandresolvingin
~2weeks
with
dose
interruptio
n,reduction,
discontin
uatio
n,or
delay.Capillaryleak
syndromehasbeen
repo
rted
[112]
125Cardiom
yopathy:
medianon
setinmelanom
apatientsforsing
le-agent
tram
etinib
~2mon
ths(2–22weeks)and~8
mon
ths(~1–25
months)whenused
incombinatio
nwith
dabrafenib,in
patientswith
NSCLC6.7mon
ths(1.4–14.1months).P
neum
onitis:mediantim
etoinitialpresentatio
ninmelanom
apatients~5
months(2
to~6
months).R
iskof
GIp
erforatio
nis0.3%
when
administeredwith
dabrafenib.G
rade
3/4hyperglycemiareported
whenused
incombinatio
nwith
dabrafenib
[170]
126Highestincidenceof
cardiomyopathyin
patientsreceivingtrastuzumab
with
ananthracycline.Reversibleupon
discontin
uatio
nof
trastuzumab
[81,
96]
127Differentiatio
nsyndromeiscommon
lyassociated
with
thedevelopm
entofh
yperleuk
ocytosis,pulmon
aryedem
a,generalized
edem
a,headache,bon
epain,and
renalfailure;bim
odalwith
peaksoccurringinthefirstand
thirdweeks
afterthe
startoftherapy.M
anagem
entincludessteroids,w
ithor
with
outdiuretics,andpossiblediscontin
uatio
nof
tretinoin,dependingon
severity
[59,
153]
16 Complications and Toxicities Associated with Cancer Therapies in the Intensive Care Unit 215
Tab
le1H
Neuro
Cardiac
Pulmon
ary
Renal
GI
Endocrine
Miscellaneous
Notes
Encephalopathy
Seizures
Heartfailure
Thromboembolism
Arrhythmias
QTprolongation
PericardialeffusionsSeverehypertension
Pneumonitis
Pulmonaryedema
Pulmonaryhypertension
PleuraleffusionsOrganizingpneumonia
Diffusealveolarhemorrhage
SIADH�hyponatremia
Renalfailure
Hemorrhagiccystitis
Bowelperforation
Neutropeniccolitis
Pancreatitis
Hepatotoxicity
Adrenalinsufficiency
Hypophysitis
Hyperglycemia
Thyroiddisorders
Cytokinereleasesyndrome
Differentiationsyndrome
Opportunisticinfections
BleedingðsevereÞRhabdomyolysis
Stevens�JohnsonsyndromeorToxicepidermalnecrolysis
Vandetanib
XX
XX
XX
XX
XX
XSee
Note12
8
Vem
urafenib
XX
XX
XX
XSee
Note129
Vinblastin
eX
See
Note13
0
Vincristin
eX
XX
XSee
Note13
1
Vinorelbine
XX
XX
XX
See
Note132
Vismodegib
XX
See
Note13
3
Vorinostat
XX
XSee
Note134
128Ischem
iccerebrovasculareventshave
been
reported.R
PLShasbeen
reported
–mon
itorforheadache,seizure,lethargy,andhy
pertension
.Optim
izeserum
potassium,m
agnesium
,and
calcium
levelspriorto
andduring
therapy.Rarecasesof
GIperforation.
Due
tolong
half-life(19days),adversereactio
ns,including
QTprolongatio
n,may
resolveslow
ly[214,2
54]
129Optim
izeserumpotassium,m
agnesium
,and
calciumlevelspriortoandduring
therapytoreduce
risk
ofcardiotoxicity.A
INandATNhave
been
reported.H
ypersensitivity:anaphylaxisand
DRESSsynd
romehave
been
reported.P
ancreatitisgenerally
occurswith
in2weeks
oftreatm
entinitiatio
n[90,
157,
251,25
5,25
6]130Paralyticileus
andob
structionmay
occur,although
toalesser
extent
than
thatob
served
with
othervincaalkaloids
131Kno
wntoaffectthecranialnervesresulting
inptosis,diplopia,andfacialpalsies.Paresthesiasinvo
lvingthehandsandfeetoftenoccurwith
inweeks
oftherapyanddependingon
severity
andmay
requireseveralm
onthstoresolvefollo
wingdrug
discon
tinuatio
n.Lossof
motor
invo
lvem
entispo
ssibleas
well(i.e.,footandhand
drop
,lossof
deep
tend
onreflexes,w
eakn
essinthe
lowerandupperextremities).AcuteGIsym
ptom
ssuch
asconstip
ationandabdominalpaincommonlyoccurw
ithinafewdays
oftherapy,with
moreseriousGItox
icities
includ
ingadynam
icileus
andbowelobstruction.
SIA
DH-induced
hyponatrem
iahasledto
seizures
[200]
132May
causesevere
paralytic
ileus
[44,
188]
133May
causeCPKelevations;rareoccurrence
ofrhabdomyo
lysis[88]
134QTprolon
gatio
nisaclasseffectof
HDACinhibitors,alth
ough
theincidencemay
belower
than
initially
repo
rted.O
ptim
izeserum
potassium
andmagnesium
levelspriorto
anddu
ring
therapy[205]
5-FU,5
-fluorouracil;
AIN
,acuteinterstitialnephritis;ALK,anaplastic
lymphom
akinase;ALT
,alanine
transaminase;AST,
aspartateam
inotransferase;ATN,acutetubu
larnecrosis;BTK,
Bruton’styrosine
kinase;C
D4,clustero
fdifferentiatio
n4;CLL,chroniclymphocyticleukem
ia;C
MV,cytom
egalovirus;C
NS,centralnervoussystem
;COPD,chronicobstructivepulm
onary
disease;
CPK,creatin
eph
osph
okinase;
CRS,cytokine
releasesyndrome;
CVA,cerebrov
ascularaccident;DLCO,diffusingcapacity
ofcarbon
mon
oxide;
DRESS,drug
reactio
nwith
eosinophiliaandsystem
icsymptom
s;EBV,E
pstein-Barrv
irus;E
KG,electrocardiogram
;FVC,forcedvitalcapacity
;GI,gastrointestinal;H
BV,hepatitisBvirus;HDAC,histone
deacetylase;
HF,heartfailure;H
LH,hem
ophagocytic
lymphohistio
cytosis;HMG-CoA
,hydroxymethylglutarylcoenzym
eA;H
US,hem
olyticurem
icsyndrome;ICANS,immuneeffector
cell-associated
neurotoxicity
syndrome;ILD,interstitiallung
disease;IV,intravenous;JC
virus,John
Cunningham
virus;LMWH,low
molecular
weightheparin;
LVEF,
leftventricularejectio
nfractio
n;MAS,macrophageactiv
ationsyndrome;
MI,myocardialinfarctio
n;NSCLC,non-sm
allcelllung
cancer;PD-1,programmed
celldeath1;
PJP,Pneum
ocystis
jirovecipneumonia;PK,
pharmacokinetics;
PML,progressivemultifocal
leukoencephalopathy;
REMS,risk
evaluatio
nandmitigatio
nstrategy;RPLS,reversible
posteriorleuk
oencephalopathysyndrome;
SJS,
Stevens-Johnson
syndrome;
TB,tuberculosis;TBI,totalbody
irradiation;
TEN,toxicepidermal
necrolysis;TMA,thrombotic
microangiopathy;TSH,thyroid-stim
ulatinghorm
one;
TTP,
thrombo
ticthrombo
cytopenicpu
rpura;ULN,u
pper
limitof
norm
al;V
OD,v
eno-occlusivedisease;VTE,v
enou
sthrombo
embolism;V
ZV,v
aricellazoster
virus
216 M. J. Rivera et al.
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