AFP-values of healthy newborns until the age of two years › workspace › uploads ›...
87
APPENDIX F Classifications 1. AFP Normal values 3 2. HCG issue 7 3. Toxicity criteria: Criteria of Adverse Events v 3.0 (CTCAE) 11 4. Maximal acute morbidity during radiotherapy / CTC Criteria 83 5. Pathology 85 6. Ototoxicity: Brock/CTC (SIOP) Grading 87
Transcript of AFP-values of healthy newborns until the age of two years › workspace › uploads ›...
-
APPENDIX F
Classifications
1. AFP Normal values 32. HCG issue 73. Toxicity criteria: Criteria of Adverse Events v 3.0
(CTCAE) 11
4. Maximal acute morbidity during radiotherapy / CTC Criteria
83
5. Pathology 856. Ototoxicity: Brock/CTC (SIOP) Grading 87
-
ALPHAALPHA--FETOPROTEINFETOPROTEIN
•• glycoprotein (MW 70.000 d)glycoprotein (MW 70.000 d)•• binding protein in fetus (yolk sac, liver, intestine)binding protein in fetus (yolk sac, liver, intestine)
Measurement Techniques: immunoassaysMeasurement Techniques: immunoassays
Half life: 5 daysHalf life: 5 days
Normally elevated during:Normally elevated during:-- gestation in fetus and mothergestation in fetus and mother-- after birth with levels falling rapidlyafter birth with levels falling rapidly up to 6 months of ageup to 6 months of age
Marker for:Marker for: Liver tumorsLiver tumors NG NG GCTsGCTs (yolk sac, (yolk sac, embryonalembryonal ca, mixed)ca, mixed)
Normal values: < 15 mg/mlNormal values: < 15 mg/ml
Conversion of units
unit arithmetic operation
unit
ng/ml x 1 = µg/l µg/l x 1 = ng/ml
ng/ml x 0.83 = kU/l IU/l x 1.205 = ng/ml
µg/ml x 830 = kU/l IU/l x 0.0012 = µg/ml
25 ng/ml = 20.75 kU/l
1000 ng/ml = 830 kU/l
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.1 Seite 1 von 3
Appendix F page 3/87
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Serum AFP-values in healthy premature infants
and aged up to 2 years Age (days) AFP-median (ng/ml) AFP 95% Intervall (ng/ml)half-life (days) 0 158125 31261 - 799834 1 140605 27797 - 711214 2 125026 24717 - 732412 3 111173 21979 - 562341 4 98855 19543 - 500035 6 5 87902 17371 - 444631 6 77625 15346 - 392645 7 69183 12589 - 349945 8-14 43401 6039 - 311889 15-21 19230 2667 - 151356 22-28 12246 1164 - 118850 14 29-45 5129 389 - 79433 46-60 2443 91 - 39084 61-90 1047 19 - 21878 91-120 398 9 - 18620 28 121-150 193 4 - 8318 151-180 108 3 - 4365 181-270 47 0,8 - 2630 271-360 18 0,4 - 832 100 361-720 4 0 - 372
Serum AFP-values in healthy premature infants95% Intervall and median
1
10
100
1000
10000
100000
1000000
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119
days
AFP
ng/m
l
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.1 Seite 2 von 3
Appendix F page 4/87
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Serum AFP-values in healthy mature newborns and aged up to 2 years
age (days) AFP-median (ng/ml) AFP 95% interval
(ng/ml) half-life (days)0 41687 9120 - 190546 1 36391 7943 - 165959 2 31769 6950 - 144544 3 27733 6026 - 125893 4 24210 5297 - 109648 5 21135 4624 - 96605 5.1 6 18450 4037 - 84334 7 16107 3524 - 73621 8-14 9333 1480 - 58887 15-21 3631 575 - 22910 22-28 1396 316 - 6310 29-45 417 30 - 5754 14 46-60 178 16 - 1995 61-90 80 6 - 1045 28 91-120 36 3 - 417 121-150 20 2 - 216 42 151-180 13 1.25 - 129 181-720 8 0.8 - 87
Serum AFP-values in healthy mature newborns95% Intervall and median
1
10
100
1000
10000
100000
1000000
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119
days
AFP
ng/
ml
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.1 Seite 3 von 3
Appendix F page 5/87
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Appendix F page 6/87
-
TECHNICAL ISSUES ON MEASUREMENTS OF MARKERS
Human Chorionic Gonadotropin (HCG)
A correct Interpretation of Markers is based on a clear definition of site of CSF
sampling for HCG, as well as the timing with respect to surgery and with respect to
serum sampling;
HCG (Human Chorionic Gonadotropin) is an hormone produced physiologically by
placenta to maintain pregnancy. It’s a glycoprotein (Molecular Weight 40000 daltons)
composed by 2 parts: α and β; the first is structurally common to other hormones
(LH, FSH); while the second component has different characteristic within these
hormones. The following simplified schema is representing the HCG molecule with its
parts and the main site of attack for antibodies used in current assays.
TOTAL HCG Free B submit
Free
Free - -Capture antibody
Tracer
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.2 Seite 1 von 3
Appendix F page 7/87
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In pathological conditions, HCG is a marker for placental tumours, fetal diseases and
GCTs, as it’s produced by trophoblastic components contained within these tumors.
Its half-life is 16 hours; it is not supposed to be present in CSF of normal subjects
and in healthy subjects serum levels of HCG are < 5mUI/ml.
Summarizing the characteristic of HCG both in physiologic and pathologic conditions,
taking into account its structure and the facts that it can be found as a dimmer (= full
molecule) or as fragments of it ( beta sub-units ), considering the pattern of secretion
of HCG by GCTs, it’s necessary to be aware of specificity and sensitivity of
immunoassays assays methods used to determine it remembering that:
HCG or intact HCG: it assays only the dimmer HCG and measurements units are mUI/ml.
β HCG free: only assays the β free sub-unit of hCG; measurements units: ng/ml.
Total HCG or so called “βHCG”: it simultaneously assays HCG and various populations of βHCG (free and nicked);
measurement Units mUI/ml.
Terminology used in current oncological literature or in the past studies (SIOP ’86)
refers to “βHCG”; in new study we suggest to use the new terminology: “Total HCG” to indicate the levels of HCG (dimer) and β free subunits making sure that the assays methods used are consistent and so on the measurements units.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.2 Seite 2 von 3
Appendix F page 8/87
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At present there are around the world > 50 commercial kits for HCG ; most of them
measure both dimer and free β HCG (Total HCG) and value is expressed in mUI/ml; more sophisticated laboratories are able to measure separately dimmer HCG
(mUI/ml) and free β HCG (ng/ml) with most sensitive methods (It’s very important that
each oncological center treating intra and extracranial GCTs is aware of potential and
limits of the kits used in their own lab. and be informed if the kit is able to detect beta
subunits (free or as a dimer), or only intact HCG or both. A method able to detect
only intact HCG is then not appropriate for GCTs especially for Germinomas.
Furthermore is very important that all the assays are referring to an international
standard. The final recommendations for HCG determination are the following:
a) Refer to International standard for interpretation of results
b) make sure that appropriate preservation rules and timing of
samples are observed for best detection of free β and dimer
because half life is 16 hours and if you perform the test after a
prolonged stay after sampling, the levels could be underestimate.
--HUMAN CHORIONIC GONADOTROPIN (HCG)HUMAN CHORIONIC GONADOTROPIN (HCG)
HCG: produced by placenta (HCG: produced by placenta ( hormones to maintain pregnancy)hormones to maintain pregnancy)
HalfHalf--life: 16 hourslife: 16 hours
NV: NV: serum < 5serum < 5 mUImUI/ml/mlCSF: absentCSF: absent
Marker for:Marker for: -- PLACENTAL TUMORS, Fetal diseases (Downs s.)PLACENTAL TUMORS, Fetal diseases (Downs s.)-- NGNG GCTsGCTs ((ChoriocaChorioca, , embryonalembryonal ca, mixed)ca, mixed)-- PurePure Germinomas Germinomas (
-
Appendix F page 10/87
-
Can
cer T
hera
py E
valu
atio
n P
rogr
am, C
omm
on T
erm
inol
ogy
Crit
eria
for A
dver
se E
vent
s, V
ersi
on 3
.0, D
CTD
, NC
I, N
IH, D
HH
S
M
arch
31,
200
3 (h
ttp://
ctep
.can
cer.g
ov),
Pub
lish
Dat
e: A
ugus
t 9, 2
006
Com
mon
Ter
min
olog
y C
riter
ia fo
r Adv
erse
Eve
nts
v3.0
(CTC
AE)
Pu
blis
h D
ate:
Aug
ust 9
, 200
6 Q
uick
Ref
eren
ce
The
NC
I C
omm
on T
erm
inol
ogy
Crit
eria
for
Adv
erse
Eve
nts
v3.0
is
a de
scrip
tive
term
inol
ogy
whi
ch c
an b
e ut
ilize
d fo
r A
dver
se E
vent
(A
E)
repo
rting
. A
gra
ding
(se
verit
y) s
cale
is
prov
ided
for e
ach
AE
term
.
Com
pone
nts
and
Org
aniz
atio
n
CA
TEG
OR
Y A
CA
TEG
OR
Y is
a b
road
cla
ssifi
catio
n of
AE
s ba
sed
on
anat
omy
and/
or p
atho
phys
iolo
gy.
With
in e
ach
CA
TEG
OR
Y,
AE
s ar
e lis
ted
acco
mpa
nied
by
thei
r de
scrip
tions
of
seve
rity
(Gra
de).
Adv
erse
Eve
nt T
erm
s A
n A
E is
any
unf
avor
able
and
uni
nten
ded
sign
(in
clud
ing
an
abno
rmal
labo
rato
ry fi
ndin
g), s
ympt
om, o
r di
seas
e te
mpo
rally
as
soci
ated
with
the
use
of
a m
edic
al t
reat
men
t or
pro
cedu
re
that
may
or
may
not
be
cons
ider
ed r
elat
ed t
o th
e m
edic
al
treat
men
t or
pro
cedu
re.
An
AE
is
a te
rm t
hat
is a
uni
que
repr
esen
tatio
n of
a
spec
ific
even
t us
ed
for
med
ical
do
cum
enta
tion
and
scie
ntifi
c an
alys
es.
Eac
h A
E
term
is
m
appe
d to
a
Med
DR
A
term
an
d co
de.
AE
s ar
e lis
ted
alph
abet
ical
ly w
ithin
CA
TEG
OR
IES
.
Shor
t AE
Nam
e Th
e ‘S
HO
RT
NA
ME’ c
olum
n is
new
and
it
is u
sed
to s
impl
ify
docu
men
tatio
n of
AE
nam
es o
n C
ase
Rep
ort F
orm
s.
Supr
a-or
dina
te T
erm
s
A s
upra
-ord
inat
e te
rm is
loca
ted
with
in a
CA
TEG
OR
Y an
d is
a
grou
ping
ter
m b
ased
on
dise
ase
proc
ess,
sig
ns,
sym
ptom
s,
or d
iagn
osis
. A
sup
ra-o
rdin
ate
term
is
follo
wed
by
the
wor
d ‘S
elec
t’ an
d is
acc
ompa
nied
by
spec
ific
AEs
tha
t ar
e al
l re
late
d to
th
e su
pra-
ordi
nate
te
rm.
Sup
ra-o
rdin
ate
term
s pr
ovid
e cl
uste
ring
and
cons
iste
nt r
epre
sent
atio
n of
Gra
de fo
r re
late
d A
Es.
S
upra
-ord
inat
e te
rms
are
not
AE
s,
are
not
map
ped
to a
Med
DR
A te
rm a
nd c
ode,
can
not b
e gr
aded
and
ca
nnot
be
used
for r
epor
ting.
REM
AR
K
A ‘R
EM
AR
K’ i
s a
clar
ifica
tion
of a
n A
E.
ALS
O C
ON
SID
ER
An
‘ALS
O C
ON
SID
ER
’ in
dica
tes
addi
tiona
l A
Es
that
are
to
be
grad
ed if
they
are
clin
ical
ly s
igni
fican
t.
NAV
IGA
TIO
N N
OTE
A
‘N
AV
IGA
TIO
N N
OTE
’ in
dica
tes
the
loca
tion
of a
n A
E t
erm
w
ithin
th
e C
TCA
E
docu
men
t. It
lists
si
gns/
sym
ptom
s al
phab
etic
ally
and
the
CTC
AE
ter
m w
ill a
ppea
r in
the
sam
e C
ATE
GO
RY
unle
ss th
e ‘N
AV
IGA
TIO
N N
OTE
’ sta
tes
diffe
rent
ly.
Gra
des
Gra
de r
efer
s to
the
sev
erity
of
the
AE
. Th
e C
TCA
E v
3.0
disp
lays
Gra
des
1 th
roug
h 5
with
uni
que
clin
ical
des
crip
tions
of
sev
erity
for e
ach
AE
bas
ed o
n th
is g
ener
al g
uide
line:
G
rade
1
Mild
AE
G
rade
2
Mod
erat
e A
E
Gra
de 3
S
ever
e A
E
Gra
de 4
Li
fe-th
reat
enin
g or
dis
ablin
g A
E
Gra
de 5
D
eath
rela
ted
to A
E
A S
emi-c
olon
indi
cate
s ‘o
r’ w
ithin
the
desc
riptio
n of
the
grad
e.
An
‘Em
das
h’ (—
) ind
icat
es a
gra
de n
ot a
vaila
ble.
N
ot a
ll G
rade
s ar
e ap
prop
riate
for
all
AE
s. T
here
fore
, so
me
AE
s ar
e lis
ted
with
fe
wer
th
an
five
optio
ns
for
Gra
de
sele
ctio
n.
Gra
de 5
G
rade
5
(Dea
th)
is
not
appr
opria
te
for
som
e A
Es
and
ther
efor
e is
not
an
optio
n.
The
DE
ATH
CA
TEG
OR
Y is
new
. O
nly
one
Sup
ra-o
rdin
ate
term
is li
sted
in th
is C
ATE
GO
RY:
‘Dea
th n
ot a
ssoc
iate
d w
ith
CTC
AE
te
rm
– S
elec
t’ w
ith
4 A
E
optio
ns:
Dea
th
NO
S;
Dis
ease
pro
gres
sion
NO
S; M
ulti-
orga
n fa
ilure
; Sud
den
deat
h.
Impo
rtan
t: •
Gra
de 5
is th
e on
ly a
ppro
pria
te G
rade
• Th
is A
E is
to b
e us
ed in
the
situ
atio
n w
here
a
deat
h
1.
cann
ot b
e re
porte
d us
ing
a C
TCA
E v
3.0
term
ass
ocia
ted
with
Gra
de 5
, or
2.
cann
ot
be
repo
rted
with
in
a C
TCA
E
CA
TEG
OR
Y as
‘Oth
er (S
peci
fy)’
Con
tent
s A
LLE
RG
Y/IM
MU
NO
LOG
Y...
......
......
......
......
......
......
.....
1 A
UD
ITO
RY
/EAR
......
......
......
......
......
......
......
......
......
......
2 B
LOO
D/B
ON
E M
AR
RO
W...
......
......
......
......
......
......
......
4 C
AR
DIA
C A
RR
HY
THM
IA...
......
......
......
......
......
......
......
.5
CA
RD
IAC
GEN
ER
AL
......
......
......
......
......
......
......
......
....7
C
OA
GU
LATI
ON
......
......
......
......
......
......
......
......
......
....1
0 C
ON
STI
TUTI
ON
AL
SY
MP
TOM
S...
......
......
......
......
.....
11
DE
ATH
......
......
......
......
......
......
......
......
......
......
......
......
13
DE
RM
ATO
LOG
Y/S
KIN
......
......
......
......
......
......
......
.....
14
EN
DO
CR
INE
......
......
......
......
......
......
......
......
......
......
...17
G
AST
RO
INTE
STI
NA
L....
......
......
......
......
......
......
......
...19
G
RO
WTH
AN
D D
EV
ELO
PM
EN
T....
......
......
......
......
....2
9
HE
MO
RR
HA
GE
/BLE
ED
ING
......
......
......
......
......
......
...30
H
EP
ATO
BILI
AR
Y/P
AN
CR
EA
S...
......
......
......
......
......
..34
IN
FEC
TIO
N...
......
......
......
......
......
......
......
......
......
......
..35
LY
MP
HA
TIC
S...
......
......
......
......
......
......
......
......
......
....3
8 M
ETA
BOLI
C/L
AB
OR
ATO
RY
......
......
......
......
......
......
..40
M
US
CU
LOS
KE
LETA
L/S
OFT
TIS
SU
E...
......
......
......
...43
N
EU
RO
LOG
Y...
......
......
......
......
......
......
......
......
......
....4
7 O
CU
LAR
/VIS
UA
L....
......
......
......
......
......
......
......
......
....5
2 P
AIN
......
......
......
......
......
......
......
......
......
......
......
......
....5
5 P
ULM
ON
AR
Y/U
PP
ER
RE
SP
IRA
TOR
Y...
......
......
......
.56
RE
NA
L/G
EN
ITO
UR
INA
RY
......
......
......
......
......
......
......
60
SE
CO
ND
AR
Y M
ALI
GN
AN
CY
......
......
......
......
......
......
.63
SE
XUA
L/R
EP
RO
DU
CTI
VE
FU
NC
TIO
N...
......
......
......
64
SU
RG
ER
Y/IN
TRA
-OP
ER
ATIV
E IN
JUR
Y...
......
......
....6
6 S
YN
DR
OM
ES
......
......
......
......
......
......
......
......
......
......
.68
VA
SC
ULA
R...
......
......
......
......
......
......
......
......
......
......
..70
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 1 von 72
Appendix F page 11/87
-
A
LLER
GY/
IMM
UN
OLO
GY
Page
1 o
f 1
G
rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 1 -
Mar
ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
t 9, 2
006
Alle
rgic
reac
tion/
hy
pers
ensi
tivity
(in
clud
ing
drug
feve
r)
Alle
rgic
reac
tion
Tran
sien
t flu
shin
g or
ra
sh; d
rug
feve
r <38
°C
(<10
0.4°
F)
Ras
h; fl
ushi
ng; u
rtica
ria;
dysp
nea;
dru
g fe
ver
≥38°
C (≥
100.
4°F)
Sym
ptom
atic
br
onch
ospa
sm, w
ith o
r w
ithou
t urti
caria
; pa
rent
eral
med
icat
ion(
s)
indi
cate
d; a
llerg
y-re
late
d ed
ema/
angi
oede
ma;
hy
pote
nsio
n
Anap
hyla
xis
Dea
th
REM
ARK: U
rtica
ria w
ith m
anife
stat
ions
of a
llerg
ic o
r hyp
erse
nsiti
vity
reac
tion
is g
rade
d as
Alle
rgic
reac
tion/
hype
rsen
sitiv
ity (i
nclu
ding
dru
g fe
ver).
ALS
O C
ON
SID
ER: C
ytok
ine
rele
ase
synd
rom
e/ac
ute
infu
sion
reac
tion.
Alle
rgic
rhin
itis
(in
clud
ing
snee
zing
, na
sal s
tuffi
ness
, po
stna
sal d
rip)
Rhi
nitis
M
ild, i
nter
vent
ion
not
indi
cate
d
Mod
erat
e, in
terv
entio
n in
dica
ted
—
—
—
REM
ARK: R
hini
tis a
ssoc
iate
d w
ith o
bstru
ctio
n or
ste
nosi
s is
gra
ded
as O
bstru
ctio
n/st
enos
is o
f airw
ay –
Sel
ect i
n th
e P
ULM
ON
AR
Y/U
PP
ER
RE
SP
IRA
TOR
Y C
ATE
GO
RY
.
Aut
oim
mun
e re
actio
n A
utoi
mm
une
reac
tion
Asy
mpt
omat
ic a
nd
sero
logi
c or
oth
er
evid
ence
of a
utoi
mm
une
reac
tion,
with
nor
mal
or
gan
func
tion
and
inte
rven
tion
not i
ndic
ated
Evi
denc
e of
aut
oim
mun
e re
actio
n in
volv
ing
a no
n-es
sent
ial o
rgan
or
func
tion
(e.g
., hy
poth
yroi
dism
)
Rev
ersi
ble
auto
imm
une
reac
tion
invo
lvin
g fu
nctio
n of
a m
ajor
org
an o
r oth
er
adve
rse
even
t (e.
g.,
trans
ient
col
itis
or
anem
ia)
Aut
oim
mun
e re
actio
n w
ith
life-
thre
aten
ing
cons
eque
nces
Dea
th
ALS
O C
ON
SID
ER: C
oliti
s; H
emog
lobi
n; H
emol
ysis
(e.g
., im
mun
e he
mol
ytic
ane
mia
, dru
g-re
late
d he
mol
ysis
); Th
yroi
d fu
nctio
n, lo
w (h
ypot
hyro
idis
m).
Ser
um s
ickn
ess
Ser
um s
ickn
ess
—
—
Pre
sent
—
D
eath
NA
VIG
ATI
ON
NO
TE: S
plen
ic fu
nctio
n is
gra
ded
in th
e B
LOO
D/B
ON
E M
AR
RO
W C
ATE
GO
RY
.
NA
VIG
ATI
ON
NO
TE: U
rtica
ria a
s an
isol
ated
sym
ptom
is g
rade
d as
Urti
caria
(hiv
es, w
elts
, whe
als)
in th
e D
ER
MA
TOLO
GY
/SK
IN C
ATE
GO
RY
.
Vas
culit
is
Vas
culit
is
Mild
, int
erve
ntio
n no
t in
dica
ted
Sym
ptom
atic
, non
-st
eroi
dal m
edic
al
inte
rven
tion
indi
cate
d
Ste
roid
s in
dica
ted
Isch
emic
cha
nges
; am
puta
tion
indi
cate
d D
eath
Alle
rgy/
Imm
unol
ogy
– O
ther
(Spe
cify
, __)
Al
lerg
y –
Oth
er (S
peci
fy)
Mild
M
oder
ate
Seve
re
Life
-thre
aten
ing;
dis
ablin
g D
eath
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 2 von 72
Appendix F page 12/87
-
A
UD
ITO
RY/
EAR
Pa
ge 1
of 2
Gra
de
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 2 -
Mar
ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
t 9, 2
006
NA
VIG
ATI
ON
NO
TE: E
arac
he (o
talg
ia) i
s gr
aded
as
Pai
n –
Sel
ect i
n th
e P
AIN
CA
TEG
OR
Y.
Hea
ring:
pa
tient
s w
ith/w
ithou
t ba
selin
e au
diog
ram
and
en
rolle
d in
a m
onito
ring
prog
ram
1
Hea
ring
(mon
itorin
g pr
ogra
m)
Thre
shol
d sh
ift o
r los
s of
15
– 2
5 dB
rela
tive
to
base
line,
ave
rage
d at
2
or m
ore
cont
iguo
us te
st
frequ
enci
es in
at l
east
on
e ea
r; or
sub
ject
ive
chan
ge in
the
abse
nce
of
a G
rade
1 th
resh
old
shift
Thre
shol
d sh
ift o
r los
s of
>2
5 –
90 d
B, a
vera
ged
at
2 co
ntig
uous
test
fre
quen
cies
in a
t lea
st
one
ear
Adu
lt on
ly: T
hres
hold
shi
ft of
>25
– 9
0 dB
, ave
rage
d at
3 c
ontig
uous
test
fre
quen
cies
in a
t lea
st
one
ear
Ped
iatri
c:
Hea
ring
loss
suf
ficie
nt to
in
dica
te th
erap
eutic
in
terv
entio
n, in
clud
ing
hear
ing
aids
(e.g
., ≥2
0 dB
bi
late
ral H
L in
the
spee
ch
frequ
enci
es; ≥
30 d
B un
ilate
ral H
L; a
nd
requ
iring
add
ition
al
spee
ch-la
ngua
ge re
late
d se
rvic
es)
Adu
lt on
ly: P
rofo
und
bila
tera
l hea
ring
loss
(>
90 d
B)
Ped
iatri
c:
Aud
iolo
gic
indi
catio
n fo
r co
chle
ar im
plan
t and
re
quiri
ng a
dditi
onal
sp
eech
-lang
uage
rela
ted
serv
ices
—
REM
ARK: P
edia
tric
reco
mm
enda
tions
are
iden
tical
to th
ose
for a
dults
, unl
ess
spec
ified
. For
chi
ldre
n an
d ad
oles
cent
s (≤
18 y
ears
of a
ge) w
ithou
t a b
asel
ine
test
, pre
-exp
osur
e/pr
e-tre
atm
ent h
earin
g sh
ould
be
cons
ider
ed to
be
90
dB
) —
REM
ARK: P
edia
tric
reco
mm
enda
tions
are
iden
tical
to th
ose
for a
dults
, unl
ess
spec
ified
. For
chi
ldre
n an
d ad
oles
cent
s (≤
18 y
ears
of a
ge) w
ithou
t a b
asel
ine
test
, pre
-exp
osur
e/pr
e-tre
atm
ent h
earin
g sh
ould
be
cons
ider
ed to
be
-
A
UD
ITO
RY/
EAR
Pa
ge 2
of 2
Gra
de
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 3 -
Mar
ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
t 9, 2
006
Tinn
itus
Tinn
itus
—
Tinn
itus
not i
nter
ferin
g w
ith A
DL
Tinn
itus
inte
rferin
g w
ith
ADL
Dis
ablin
g —
ALS
O C
ON
SID
ER: H
earin
g: p
atie
nts
with
/with
out b
asel
ine
audi
ogra
m a
nd e
nrol
led
in a
mon
itorin
g pr
ogra
m1 ;
Hea
ring:
pat
ient
s w
ithou
t bas
elin
e au
diog
ram
and
not
enr
olle
d in
a
mon
itorin
g pr
ogra
m1 .
Aud
itory
/Ear
– O
ther
(S
peci
fy, _
_)
Aud
itory
/Ear
– O
ther
(S
peci
fy)
Mild
M
oder
ate
Sev
ere
Life
-thre
aten
ing;
dis
ablin
g D
eath
1 D
rug-
indu
ced
otot
oxic
ity s
houl
d be
dis
tingu
ishe
d fro
m a
ge-r
elat
ed th
resh
old
decr
emen
ts o
r unr
elat
ed c
ochl
ear i
nsul
t. W
hen
cons
ider
ing
whe
ther
an
adve
rse
even
t has
occ
urre
d, it
is
first
nec
essa
ry to
cla
ssify
the
patie
nt in
to o
ne o
f tw
o gr
oups
. (1)
The
pat
ient
is u
nder
sta
ndar
d tre
atm
ent/e
nrol
led
in a
clin
ical
tria
l <2.
5 ye
ars,
and
has
a 1
5 dB
or g
reat
er th
resh
old
shift
ave
rage
d ac
ross
two
cont
iguo
us fr
eque
ncie
s; o
r (2)
The
pat
ient
is u
nder
sta
ndar
d tre
atm
ent/e
nrol
led
in a
clin
ical
tria
l >2.
5 ye
ars,
and
the
diffe
renc
e be
twee
n th
e ex
pect
ed a
ge-
rela
ted
and
the
obse
rved
thre
shol
d sh
ifts
is 1
5 dB
or g
reat
er a
vera
ged
acro
ss tw
o co
ntig
uous
freq
uenc
ies.
Con
sult
stan
dard
refe
renc
es fo
r app
ropr
iate
age
- and
gen
der-s
peci
fic
hear
ing
norm
s, e
.g.,
Mor
rell,
et a
l. A
ge- a
nd g
ende
r-spe
cific
refe
renc
e ra
nges
for h
earin
g le
vel a
nd lo
ngitu
dina
l cha
nges
in h
earin
g le
vel.
Jour
nal o
f the
Aco
ustic
al S
ocie
ty o
f Am
eric
a 10
0:19
49-1
967,
199
6; o
r Sho
tland
, et a
l. R
ecom
men
datio
ns fo
r can
cer p
reve
ntio
n tri
als
usin
g po
tent
ially
oto
toxi
c te
st a
gent
s. J
ourn
al o
f Clin
ical
Onc
olog
y 19
:165
8-16
63, 2
001.
In th
e ab
senc
e of
a b
asel
ine
prio
r to
initi
al tr
eatm
ent,
subs
eque
nt a
udio
gram
s sh
ould
be
refe
renc
ed to
an
appr
opria
te d
atab
ase
of n
orm
als.
AN
SI.
(199
6)
Am
eric
an N
atio
nal S
tand
ard:
Det
erm
inat
ion
of o
ccup
atio
nal n
oise
exp
osur
e an
d es
timat
ion
of n
oise
-indu
ced
hear
ing
impa
irmen
t, A
NS
I S 3
.44-
1996
. (S
tand
ard
S 3
.44)
. New
Yor
k:
Am
eric
an N
atio
nal S
tand
ards
Inst
itute
. The
reco
mm
ende
d A
NS
I S3.
44 d
atab
ase
is A
nnex
B.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 4 von 72
Appendix F page 14/87
-
B
LOO
D/B
ON
E M
AR
RO
W
Page
1 o
f 1
G
rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
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ch 3
1, 2
003,
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lish
Dat
e: A
ugus
t 9, 2
006
Bone
mar
row
cel
lula
rity
Bon
e m
arro
w c
ellu
larit
y M
ildly
hyp
ocel
lula
r or
≤25%
redu
ctio
n fro
m
norm
al c
ellu
larit
y fo
r age
Mod
erat
ely
hypo
cellu
lar
or >
25 –
≤50
% re
duct
ion
from
nor
mal
cel
lula
rity
for
age
Sev
erel
y hy
poce
llula
r or
>50
– ≤7
5% re
duct
ion
cellu
larit
y fro
m n
orm
al fo
r ag
e
—
Dea
th
CD
4 co
unt
CD
4 co
unt
-
C
AR
DIA
C A
RR
HYT
HM
IA
Page
1 o
f 2
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rade
Adv
erse
Eve
nt
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t Nam
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AE
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ch 3
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003,
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lish
Dat
e: A
ugus
t 9, 2
006
Con
duct
ion
abno
rmal
ity/
atrio
vent
ricul
ar h
eart
bloc
k
– S
elec
t:
Con
duct
ion
abno
rmal
ity
– S
elec
t A
sym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
– A
syst
ole
– A
V B
lock
-Firs
t deg
ree
– A
V B
lock
-Sec
ond
degr
ee M
obitz
Typ
e I (
Wen
ckeb
ach)
–
AV
Blo
ck-S
econ
d de
gree
Mob
itz T
ype
II –
AV
Blo
ck-T
hird
deg
ree
(Com
plet
e A
V b
lock
) –
Con
duct
ion
abno
rmal
ity N
OS
–
Sic
k S
inus
Syn
drom
e
– S
toke
s-A
dam
s S
yndr
ome
– W
olff-
Par
kins
on-W
hite
Syn
drom
e
Non
-urg
ent m
edic
al
inte
rven
tion
indi
cate
d In
com
plet
ely
cont
rolle
d m
edic
ally
or c
ontro
lled
w
ith d
evic
e (e
.g.,
pace
mak
er)
Life
-thre
aten
ing
(e.g
., ar
rhyt
hmia
ass
ocia
ted
with
CH
F, h
ypot
ensi
on,
sync
ope,
sho
ck)
Dea
th
Pal
pita
tions
P
alpi
tatio
ns
Pre
sent
P
rese
nt w
ith a
ssoc
iate
d sy
mpt
oms
(e.g
., lig
hthe
aded
ness
, sh
ortn
ess
of b
reat
h)
—
—
—
REM
ARK: G
rade
pal
pita
tions
onl
y in
the
abse
nce
of a
doc
umen
ted
arrh
ythm
ia.
Prol
onge
d Q
Tc in
terv
al
Prol
onge
d Q
Tc
QTc
>0.
45 –
0.4
7 se
cond
Q
Tc >
0.47
– 0
.50
seco
nd; ≥
0.06
sec
ond
abov
e ba
selin
e
QTc
>0.
50 s
econ
d Q
Tc >
0.50
sec
ond;
life
-th
reat
enin
g si
gns
or
sym
ptom
s (e
.g.,
arrh
ythm
ia, C
HF,
hy
pote
nsio
n, s
hock
sy
ncop
e); T
orsa
de d
e po
inte
s
Dea
th
Sup
rave
ntric
ular
and
no
dal a
rrhyt
hmia
–
Sel
ect:
Sup
rave
ntric
ular
ar
rhyt
hmia
– S
elec
t A
sym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
Non
-urg
ent m
edic
al
inte
rven
tion
indi
cate
d
– A
trial
fibr
illat
ion
– A
trial
flut
ter
– A
trial
tach
ycar
dia/
Par
oxys
mal
Atri
al T
achy
card
ia
– N
odal
/Jun
ctio
nal
– Si
nus
arrh
ythm
ia
– Si
nus
brad
ycar
dia
– Si
nus
tach
ycar
dia
–
Sup
rave
ntric
ular
arrh
ythm
ia N
OS
–
Sup
rave
ntric
ular
ext
rasy
stol
es (P
rem
atur
e A
trial
Con
tract
ions
; Pre
mat
ure
Nod
al/J
unct
iona
l Con
tract
ions
) –
Sup
rave
ntric
ular
tach
ycar
dia
Sym
ptom
atic
and
in
com
plet
ely
cont
rolle
d m
edic
ally
, or c
ontro
lled
with
dev
ice
(e.g
., pa
cem
aker
)
Life
-thre
aten
ing
(e.g
., ar
rhyt
hmia
ass
ocia
ted
with
CH
F, h
ypot
ensi
on,
sync
ope,
sho
ck)
Dea
th
NA
VIG
ATI
ON
NO
TE: S
ynco
pe is
gra
ded
as S
ynco
pe (f
aint
ing)
in th
e N
EU
RO
LOG
Y C
ATE
GO
RY
.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 6 von 72
Appendix F page 16/87
-
C
AR
DIA
C A
RR
HYT
HM
IA
Page
2 o
f 2
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rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
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AE
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ch 3
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003,
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lish
Dat
e: A
ugus
t 9, 2
006
Vas
ovag
al e
piso
de
Vas
ovag
al e
piso
de
—
Pre
sent
with
out l
oss
of
cons
ciou
snes
s P
rese
nt w
ith lo
ss o
f co
nsci
ousn
ess
Life
-thre
aten
ing
cons
eque
nces
D
eath
Ven
tricu
lar a
rrhy
thm
ia
– S
elec
t: V
entri
cula
r arr
hyth
mia
–
Sel
ect
– Bi
gem
iny
– Id
iove
ntric
ular
rhyt
hm
– P
VC
s –
Tors
ade
de p
oint
es
– Tr
igem
iny
– V
entri
cula
r arr
hyth
mia
NO
S
– V
entri
cula
r fib
rilla
tion
–
Ven
tricu
lar f
lutte
r –
Ven
tricu
lar t
achy
card
ia
Asy
mpt
omat
ic, n
o in
terv
entio
n in
dica
ted
Non
-urg
ent m
edic
al
inte
rven
tion
indi
cate
d S
ympt
omat
ic a
nd
inco
mpl
etel
y co
ntro
lled
med
ical
ly o
r con
trolle
d w
ith d
evic
e (e
.g.,
defib
rilla
tor)
Life
-thre
aten
ing
(e.g
., ar
rhyt
hmia
ass
ocia
ted
with
CH
F, h
ypot
ensi
on,
sync
ope,
sho
ck)
Dea
th
Car
diac
Arrh
ythm
ia
– O
ther
(Spe
cify
, __)
C
ardi
ac A
rrhyt
hmia
–
Oth
er (S
peci
fy)
Mild
M
oder
ate
Sev
ere
Life
-thre
aten
ing;
di
sabl
ing
D
eath
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 7 von 72
Appendix F page 17/87
-
C
AR
DIA
C G
ENER
AL
Page
1 o
f 3
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rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
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AE
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ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
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006
NA
VIG
ATI
ON
NO
TE: A
ngin
a is
gra
ded
as C
ardi
ac is
chem
ia/in
farc
tion
in th
e C
AR
DIA
C G
EN
ER
AL
CA
TEG
OR
Y.
Car
diac
is
chem
ia/in
farc
tion
Car
diac
is
chem
ia/in
farc
tion
Asy
mpt
omat
ic a
rteria
l na
rrow
ing
with
out
isch
emia
Asy
mpt
omat
ic a
nd te
stin
g su
gges
ting
isch
emia
; st
able
ang
ina
Sym
ptom
atic
and
test
ing
cons
iste
nt w
ith is
chem
ia;
unst
able
ang
ina;
in
terv
entio
n in
dica
ted
Acu
te m
yoca
rdia
l in
farc
tion
Dea
th
Car
diac
trop
onin
I (c
TnI)
cTnI
—
—
Le
vels
con
sist
ent w
ith
unst
able
ang
ina
as
defin
ed b
y th
e m
anuf
actu
rer
Leve
ls c
onsi
sten
t with
m
yoca
rdia
l inf
arct
ion
as
defin
ed b
y th
e m
anuf
actu
rer
Dea
th
Car
diac
trop
onin
T (c
TnT)
cT
nT
0.03
– <
0.05
ng/
mL
0.05
– <
0.1
ng/m
L 0.
1 –
-
C
AR
DIA
C G
ENER
AL
Page
2 o
f 3
G
rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 8 -
Mar
ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
t 9, 2
006
Hyp
oten
sion
H
ypot
ensi
on
Cha
nges
, int
erve
ntio
n no
t in
dica
ted
Brie
f (
-
C
AR
DIA
C G
ENER
AL
Page
3 o
f 3
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rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
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AE
v3.
0
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Mar
ch 3
1, 2
003,
Pub
lish
Dat
e: A
ugus
t 9, 2
006
Rig
ht v
entri
cula
r dy
sfun
ctio
n (c
or p
ulm
onal
e)
Rig
ht v
entri
cula
r dy
sfun
ctio
n A
sym
ptom
atic
with
out
ther
apy
Asym
ptom
atic
, the
rapy
in
dica
ted
Sym
ptom
atic
cor
pu
lmon
ale,
resp
onsi
ve to
in
terv
entio
n
Sym
ptom
atic
cor
pu
lmon
ale
poor
ly
cont
rolle
d; in
terv
entio
n su
ch a
s ve
ntric
ular
ass
ist
devi
ce, o
r hea
rt tra
nspl
ant i
ndic
ated
Dea
th
Val
vula
r hea
rt di
seas
e V
alvu
lar h
eart
dise
ase
Asy
mpt
omat
ic v
alvu
lar
thic
keni
ng w
ith o
r with
out
mild
val
vula
r reg
urgi
tatio
n or
ste
nosi
s; tr
eatm
ent
othe
r tha
n en
doca
rditi
s pr
ophy
laxi
s no
t ind
icat
ed
Asy
mpt
omat
ic; m
oder
ate
regu
rgita
tion
or s
teno
sis
by im
agin
g
Sym
ptom
atic
; sev
ere
regu
rgita
tion
or s
teno
sis;
sy
mpt
oms
cont
rolle
d w
ith
med
ical
ther
apy
Life
-thre
aten
ing;
di
sabl
ing;
inte
rven
tion
(e.g
., va
lve
repl
acem
ent,
valv
ulop
last
y) in
dica
ted
Dea
th
Car
diac
Gen
eral
– O
ther
(S
peci
fy, _
_)
Car
diac
Gen
eral
– O
ther
(S
peci
fy)
Mild
M
oder
ate
Sev
ere
Life
-thre
aten
ing;
dis
ablin
g D
eath
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 10 von 72
Appendix F page 20/87
-
C
OA
GU
LATI
ON
Pa
ge 1
of 1
Gra
de
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 10
- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
DIC
(dis
sem
inat
ed
intra
vasc
ular
coa
gula
tion)
D
IC
—
Labo
rato
ry fi
ndin
gs w
ith
no b
leed
ing
Labo
rato
ry fi
ndin
gs a
nd
blee
ding
La
bora
tory
find
ings
, life
-th
reat
enin
g or
dis
ablin
g co
nseq
uenc
es (e
.g.,
CN
S
hem
orrh
age,
org
an
dam
age,
or
hem
odyn
amic
ally
si
gnifi
cant
blo
od lo
ss)
Dea
th
REM
ARK: D
IC (d
isse
min
ated
intra
vasc
ular
coa
gula
tion)
mus
t hav
e in
crea
sed
fibrin
spl
it pr
oduc
ts o
r D-d
imer
.
ALS
O C
ON
SID
ER: P
late
lets
.
Fibr
inog
en
Fibr
inog
en
-
C
ON
STIT
UTI
ON
AL
SYM
PTO
MS
Page
1 o
f 2
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rade
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erse
Eve
nt
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t Nam
e 1
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AE
v3.
0
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arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Fatig
ue
(ast
heni
a, le
thar
gy,
mal
aise
)
Fatig
ue
Mild
fatig
ue o
ver b
asel
ine
Mod
erat
e or
cau
sing
di
fficu
lty p
erfo
rmin
g so
me
ADL
Sev
ere
fatig
ue in
terfe
ring
with
AD
L D
isab
ling
—
Feve
r (in
the
abse
nce
of
neut
rope
nia,
whe
re
neut
rope
nia
is d
efin
ed a
s AN
C <
1.0
x 10
9 /L)
Feve
r 38
.0 –
39.
0°C
(1
00.4
– 1
02.2
°F)
>39.
0 –
40.0
°C
(102
.3 –
104
.0°F
) >4
0.0°
C
(>10
4.0°
F) fo
r ≤24
hrs
>4
0.0°
C
(>10
4.0°
F) fo
r >24
hrs
D
eath
REM
ARK: T
he te
mpe
ratu
re m
easu
rem
ents
list
ed a
re o
ral o
r tym
pani
c.
ALS
O C
ON
SID
ER: A
llerg
ic re
actio
n/hy
pers
ensi
tivity
(inc
ludi
ng d
rug
feve
r).
NA
VIG
ATI
ON
NO
TE: H
ot fl
ashe
s ar
e gr
aded
as
Hot
flas
hes/
flush
es in
the
EN
DO
CR
INE
CA
TEG
OR
Y.
Hyp
othe
rmia
H
ypot
herm
ia
—
35 –
>32
°C
95 –
>89
.6°F
32
– >
28°C
89
.6 –
>82
.4°
F ≤2
8 °C
82
.4°F
or l
ife-th
reat
enin
g co
nseq
uenc
es (e
.g.,
com
a, h
ypot
ensi
on,
pulm
onar
y ed
ema,
ac
idem
ia, v
entri
cula
r fib
rilla
tion)
Dea
th
Inso
mni
a In
som
nia
Occ
asio
nal d
iffic
ulty
sl
eepi
ng, n
ot in
terfe
ring
with
func
tion
Diff
icul
ty s
leep
ing,
in
terfe
ring
with
func
tion
but n
ot in
terfe
ring
with
AD
L
Freq
uent
diff
icul
ty
slee
ping
, int
erfe
ring
with
AD
L
Dis
ablin
g —
REM
ARK: I
f pai
n or
oth
er s
ympt
oms
inte
rfere
with
sle
ep, d
o N
OT
grad
e as
inso
mni
a. G
rade
prim
ary
even
t(s) c
ausi
ng in
som
nia.
Obe
sity
2 O
besi
ty
—
BM
I 25
– 29
.9 k
g/m
2 B
MI 3
0 –
39.9
9 kg
/m2
BM
I ≥40
kg/
m2
—
REM
ARK: B
MI =
(wei
ght [
kg])
/ (he
ight
[m])2
Odo
r (p
atie
nt o
dor)
Pat
ient
odo
r M
ild o
dor
Pro
noun
ced
odor
—
—
—
Rig
ors/
chills
R
igor
s/ch
ills
Mild
M
oder
ate,
nar
cotic
s in
dica
ted
Sev
ere
or p
rolo
nged
, not
re
spon
sive
to n
arco
tics
—
—
2 N
HLB
I Obe
sity
Tas
k Fo
rce.
"Clin
ical
Gui
delin
es o
n th
e Id
entif
icat
ion,
Eva
luat
ion,
and
Tre
atm
ent o
f Ove
rwei
ght a
nd O
besi
ty in
Adu
lts,"
The
Evi
denc
e R
epor
t, O
bes
Res
6:5
1S-
209S
, 199
8.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 12 von 72
Appendix F page 22/87
-
C
ON
STIT
UTI
ON
AL
SYM
PTO
MS
Page
2 o
f 2
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rade
Adv
erse
Eve
nt
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t Nam
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AE
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- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Sw
eatin
g
(dia
phor
esis
) S
wea
ting
M
ild a
nd o
ccas
iona
l Fr
eque
nt o
r dre
nchi
ng
—
—
—
ALS
O C
ON
SID
ER: H
ot fl
ashe
s/flu
shes
.
Wei
ght g
ain
W
eigh
t gai
n 5
–
-
D
EATH
Pa
ge 1
of 1
Gra
de
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 13
- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Dea
th n
ot a
ssoc
iate
d w
ith
CTC
AE
term
–
Sel
ect:
Dea
th n
ot a
ssoc
iate
d w
ith
CTC
AE
term
– S
elec
t
– D
eath
NO
S –
Dis
ease
pro
gres
sion
NO
S –
Mul
ti-or
gan
failu
re
– Su
dden
dea
th
—
—
—
—
Dea
th
REM
ARK: G
rade
5 is
the
only
app
ropr
iate
gra
de. '
Dea
th n
ot a
ssoc
iate
d w
ith C
TCA
E te
rm –
Sel
ect'
is to
be
used
whe
re a
dea
th:
1.
Can
not b
e at
tribu
ted
to a
CTC
AE
term
ass
ocia
ted
with
Gra
de 5
. 2.
C
anno
t be
repo
rted
with
in a
ny C
ATE
GO
RY
usi
ng a
CTC
AE
'Oth
er (S
peci
fy, _
_)’.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 14 von 72
Appendix F page 24/87
-
D
ERM
ATO
LOG
Y/SK
IN
Page
1 o
f 3
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rade
Adv
erse
Eve
nt
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t Nam
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AE
v3.
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arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Atro
phy,
ski
n A
troph
y, s
kin
Det
ecta
ble
Mar
ked
—
—
—
Atro
phy,
sub
cuta
neou
s fa
t At
roph
y, s
ubcu
tane
ous
fat
Det
ecta
ble
Mar
ked
—
—
—
ALS
O C
ON
SID
ER: I
ndur
atio
n/fib
rosi
s (s
kin
and
subc
utan
eous
tiss
ue).
Bru
isin
g
(in a
bsen
ce o
f Gra
de 3
or
4 th
rom
bocy
tope
nia)
Bru
isin
g
Loca
lized
or i
n a
depe
nden
t are
a G
ener
aliz
ed
—
—
—
Bur
n B
urn
Min
imal
sym
ptom
s;
inte
rven
tion
not i
ndic
ated
M
edic
al in
terv
entio
n;
min
imal
deb
ridem
ent
indi
cate
d
Mod
erat
e to
maj
or
debr
idem
ent o
r re
cons
truct
ion
indi
cate
d
Life
-thre
aten
ing
cons
eque
nces
D
eath
REM
ARK: B
urn
refe
rs to
all
burn
s in
clud
ing
radi
atio
n, c
hem
ical
, etc
.
Che
ilitis
C
heili
tis
Asym
ptom
atic
S
ympt
omat
ic, n
ot
inte
rferin
g w
ith A
DL
Sym
ptom
atic
, int
erfe
ring
with
AD
L —
—
Dry
ski
n D
ry s
kin
Asy
mpt
omat
ic
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L In
terfe
ring
with
AD
L —
—
Flus
hing
Fl
ushi
ng
Asy
mpt
omat
ic
Sym
ptom
atic
—
—
—
Hai
r los
s/al
opec
ia
(sca
lp o
r bod
y)
Alop
ecia
Th
inni
ng o
r pat
chy
Com
plet
e —
—
—
Hyp
erpi
gmen
tatio
n H
yper
pigm
enta
tion
Slig
ht o
r loc
aliz
ed
Mar
ked
or g
ener
aliz
ed
—
—
—
Hyp
opig
men
tatio
n H
ypop
igm
enta
tion
Slig
ht o
r loc
aliz
ed
Mar
ked
or g
ener
aliz
ed
—
—
—
Indu
ratio
n/fib
rosi
s (s
kin
and
subc
utan
eous
tis
sue)
Indu
ratio
n
Incr
ease
d de
nsity
on
palp
atio
n M
oder
ate
impa
irmen
t of
func
tion
not i
nter
ferin
g w
ith A
DL;
mar
ked
incr
ease
in d
ensi
ty a
nd
firm
ness
on
palp
atio
n w
ith o
r with
out m
inim
al
retra
ctio
n
Dys
func
tion
inte
rferin
g w
ith A
DL;
ver
y m
arke
d de
nsity
, ret
ract
ion
or
fixat
ion
—
—
ALS
O C
ON
SID
ER: F
ibro
sis-
cosm
esis
; Fib
rosi
s-de
ep c
onne
ctiv
e tis
sue.
Inje
ctio
n si
te re
actio
n/
extra
vasa
tion
chan
ges
Inje
ctio
n si
te re
actio
n P
ain;
itch
ing;
ery
them
a P
ain
or s
wel
ling,
with
in
flam
mat
ion
or p
hleb
itis
Ulc
erat
ion
or n
ecro
sis
that
is s
ever
e; o
pera
tive
inte
rven
tion
indi
cate
d
—
—
ALS
O C
ON
SID
ER: A
llerg
ic re
actio
n/hy
pers
ensi
tivity
(inc
ludi
ng d
rug
feve
r); U
lcer
atio
n.
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 15 von 72
Appendix F page 25/87
-
D
ERM
ATO
LOG
Y/SK
IN
Page
2 o
f 3
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rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
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AE
v3.
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- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Nai
l cha
nges
N
ail c
hang
es
Dis
colo
ratio
n; ri
dgin
g (k
oilo
nych
ias)
; pitt
ing
Par
tial o
r com
plet
e lo
ss o
f na
il(s)
; pai
n in
nai
lbed
(s)
Inte
rferin
g w
ith A
DL
—
—
NA
VIG
ATI
ON
NO
TE: P
etec
hiae
is g
rade
d as
Pet
echi
ae/p
urpu
ra (h
emor
rhag
e/bl
eedi
ng in
to s
kin
or m
ucos
a) in
the
HE
MO
RR
HA
GE
/BLE
ED
ING
CA
TEG
OR
Y.
Pho
tose
nsiti
vity
P
hoto
sens
itivi
ty
Pai
nles
s er
ythe
ma
Pai
nful
ery
them
a E
ryth
ema
with
de
squa
mat
ion
Life
-thre
aten
ing;
dis
ablin
g D
eath
Pru
ritus
/itch
ing
Pru
ritus
M
ild o
r loc
aliz
ed
Inte
nse
or w
ides
prea
d In
tens
e or
wid
espr
ead
and
inte
rferin
g w
ith A
DL
—
—
ALS
O C
ON
SID
ER: R
ash/
desq
uam
atio
n.
Ras
h/de
squa
mat
ion
R
ash
Mac
ular
or p
apul
ar
erup
tion
or e
ryth
ema
with
out a
ssoc
iate
d sy
mpt
oms
Mac
ular
or p
apul
ar
erup
tion
or e
ryth
ema
with
pr
uritu
s or
oth
er
asso
ciat
ed s
ympt
oms;
lo
caliz
ed d
esqu
amat
ion
or o
ther
lesi
ons
cove
ring
-
D
ERM
ATO
LOG
Y/SK
IN
Page
3 o
f 3
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rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
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AE
v3.
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- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Ski
n br
eakd
own/
de
cubi
tus
ulce
r D
ecub
itus
—
Lo
cal w
ound
car
e;
med
ical
inte
rven
tion
indi
cate
d
Ope
rativ
e de
brid
emen
t or
othe
r inv
asiv
e in
terv
entio
n in
dica
ted
(e.g
., hy
perb
aric
oxy
gen)
Life
-thre
aten
ing
cons
eque
nces
; maj
or
inva
sive
inte
rven
tion
indi
cate
d (e
.g.,
tissu
e re
cons
truct
ion,
flap
, or
graf
ting)
Dea
th
REM
ARK: S
kin
brea
kdow
n/de
cubi
tus
ulce
r is
to b
e us
ed fo
r los
s of
ski
n in
tegr
ity o
r dec
ubitu
s ul
cer f
rom
pre
ssur
e or
as
the
resu
lt of
ope
rativ
e or
med
ical
inte
rven
tion.
Stri
ae
Stri
ae
Mild
C
osm
etic
ally
sig
nific
ant
—
—
—
Tela
ngie
ctas
ia
Tela
ngie
ctas
ia
Few
M
oder
ate
num
ber
Man
y an
d co
nflu
ent
—
—
Ulc
erat
ion
Ulc
erat
ion
—
Sup
erfic
ial u
lcer
atio
n
-
EN
DO
CR
INE
Page
1 o
f 2
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rade
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erse
Eve
nt
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AE
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arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Adre
nal i
nsuf
ficie
ncy
Adre
nal i
nsuf
ficie
ncy
Asym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
Sym
ptom
atic
, int
erve
ntio
n in
dica
ted
Hos
pita
lizat
ion
Li
fe-th
reat
enin
g; d
isab
ling
Dea
th
REM
ARK: A
dren
al in
suffi
cien
cy in
clud
es a
ny o
f the
follo
win
g si
gns
and
sym
ptom
s: a
bdom
inal
pai
n, a
nore
xia,
con
stip
atio
n, d
iarrh
ea, h
ypot
ensi
on, p
igm
enta
tion
of m
ucou
s m
embr
anes
, pi
gmen
tatio
n of
ski
n, s
alt c
ravi
ng, s
ynco
pe (f
aint
ing)
, viti
ligo,
vom
iting
, wea
knes
s, w
eigh
t los
s. A
dren
al in
suffi
cien
cy m
ust b
e co
nfirm
ed b
y la
bora
tory
stu
dies
(low
cor
tisol
freq
uent
ly
acco
mpa
nied
by
low
ald
oste
rone
).
ALS
O C
ON
SID
ER: P
otas
sium
, ser
um-h
igh
(hyp
erka
lem
ia);
Thyr
oid
func
tion,
low
(hyp
othy
roid
ism
).
Cus
hing
oid
appe
aran
ce
(e.g
., m
oon
face
, buf
falo
hu
mp,
cen
tripe
tal o
besi
ty,
cuta
neou
s st
riae)
Cus
hing
oid
—
P
rese
nt
—
—
—
ALS
O C
ON
SID
ER: G
luco
se, s
erum
-hig
h (h
yper
glyc
emia
); P
otas
sium
, ser
um-lo
w (h
ypok
alem
ia).
Fem
iniz
atio
n of
mal
e Fe
min
izat
ion
of m
ale
—
—
Pre
sent
—
—
NA
VIG
ATI
ON
NO
TE: G
ynec
omas
tia is
gra
ded
in th
e S
EX
UA
L/R
EP
RO
DU
CTI
VE
FU
NC
TIO
N C
ATE
GO
RY
.
Hot
flas
hes/
flush
es3
Hot
flas
hes
Mild
M
oder
ate
In
terfe
ring
with
AD
L —
—
Mas
culin
izat
ion
of fe
mal
e M
ascu
liniz
atio
n of
fem
ale
—
—
Pre
sent
—
—
Neu
roen
docr
ine:
A
CTH
def
icie
ncy
AC
TH
Asy
mpt
omat
ic
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
inte
rven
tion
indi
cate
d
Sym
ptom
s in
terfe
ring
with
A
DL;
hos
pita
lizat
ion
indi
cate
d
Life
-thre
aten
ing
cons
eque
nces
(e.g
., se
vere
hyp
oten
sion
)
Dea
th
Neu
roen
docr
ine:
A
DH
sec
retio
n ab
norm
ality
(e.g
., S
IAD
H
or lo
w A
DH
)
AD
H
Asy
mpt
omat
ic
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
inte
rven
tion
indi
cate
d
Sym
ptom
s in
terfe
ring
with
AD
L Li
fe-th
reat
enin
g co
nseq
uenc
es
Dea
th
Neu
roen
docr
ine:
go
nado
tropi
n se
cret
ion
abno
rmal
ity
Gon
adot
ropi
n A
sym
ptom
atic
S
ympt
omat
ic, n
ot
inte
rferin
g w
ith A
DL;
in
terv
entio
n in
dica
ted
Sym
ptom
s in
terfe
ring
with
A
DL;
ost
eope
nia;
fra
ctur
e; in
ferti
lity
—
—
Neu
roen
docr
ine:
gr
owth
hor
mon
e se
cret
ion
abno
rmal
ity
Gro
wth
hor
mon
e
Asy
mpt
omat
ic
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
inte
rven
tion
indi
cate
d
—
—
—
Neu
roen
docr
ine:
pr
olac
tin h
orm
one
secr
etio
n ab
norm
ality
Pro
lact
in
Asy
mpt
omat
ic
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
inte
rven
tion
indi
cate
d
Sym
ptom
s in
terfe
ring
with
A
DL;
am
enor
rhea
; ga
lact
orrh
ea
—
Dea
th
3 S
loan
JA
, Lop
rinzi
CL,
Nov
otny
PJ,
Bar
ton
DL,
Lav
asse
ur B
I, W
inds
chitl
HJ,
"Met
hodo
logi
c Le
sson
s Le
arne
d fro
m H
ot F
lash
Stu
dies
," J
Clin
Onc
ol 2
001
Dec
1;1
9(23
):428
0-90
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 18 von 72
Appendix F page 28/87
-
EN
DO
CR
INE
Page
2 o
f 2
G
rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 18
- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
Pan
crea
tic e
ndoc
rine:
gl
ucos
e in
tole
ranc
e D
iabe
tes
Asy
mpt
omat
ic,
inte
rven
tion
not i
ndic
ated
S
ympt
omat
ic; d
ieta
ry
mod
ifica
tion
or o
ral a
gent
in
dica
ted
Sym
ptom
s in
terfe
ring
with
A
DL;
insu
lin in
dica
ted
Life
-thre
aten
ing
cons
eque
nces
(e.g
., ke
toac
idos
is,
hype
rosm
olar
non
-ket
otic
co
ma)
Dea
th
Par
athy
roid
func
tion,
low
(h
ypop
arat
hyro
idis
m)
Hyp
opar
athy
roid
ism
A
sym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
Sym
ptom
atic
; int
erve
ntio
n in
dica
ted
—
—
—
Thyr
oid
func
tion,
hig
h (h
yper
thyr
oidi
sm,
thyr
otox
icos
is)
Hyp
erth
yroi
dism
A
sym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
thyr
oid
supp
ress
ion
ther
apy
indi
cate
d
Sym
ptom
s in
terfe
ring
with
A
DL;
hos
pita
lizat
ion
indi
cate
d
Life
-thre
aten
ing
cons
eque
nces
(e.g
., th
yroi
d st
orm
)
Dea
th
Thyr
oid
func
tion,
low
(h
ypot
hyro
idis
m)
Hyp
othy
roid
ism
A
sym
ptom
atic
, in
terv
entio
n no
t ind
icat
ed
Sym
ptom
atic
, not
in
terfe
ring
with
AD
L;
thyr
oid
repl
acem
ent
indi
cate
d
Sym
ptom
s in
terfe
ring
with
A
DL;
hos
pita
lizat
ion
indi
cate
d
Life
-thre
aten
ing
myx
edem
a co
ma
Dea
th
End
ocrin
e –
Oth
er
(Spe
cify
, __)
E
ndoc
rine
– O
ther
(S
peci
fy)
Mild
M
oder
ate
Sev
ere
Life
-thre
aten
ing;
dis
ablin
g D
eath
SIOP CNS GCT II, Finale Version 2, 15.06.2011, Appendix F.3 Seite 19 von 72
Appendix F page 29/87
-
G
AST
RO
INTE
STIN
AL
Page
1 o
f 10
G
rade
Adv
erse
Eve
nt
Shor
t Nam
e 1
2 3
4 5
CTC
AE
v3.
0
- 19
- M
arch
31,
200
3, P
ublis
h D
ate:
Aug
ust 9
, 200
6
NA
VIG
ATI
ON
NO
TE: A
bdom
inal
pai
n or
cra
mpi
ng is
gra
ded
as P
ain
– S
elec
t in
the
PA
IN C
ATE
GO
RY
.
Ano
rexi
a A
nore
xia
Loss
of a
ppet
ite w
ithou
t al
tera
tion
in e
atin
g ha
bits
O
ral i
ntak
e al
tere
d w
ithou
t sig
nific
ant w
eigh
t lo
ss o
r mal
nutri
tion;
ora
l nu
tritio
nal s
uppl
emen
ts
indi
cate
d
Ass
ocia
ted
with
si
gnifi
cant
wei
ght l
oss
or
mal
nutri
tion
(e.g
., in
adeq
uate
ora
l cal
oric
an
d/or
flui
d in
take
); IV
flu
ids,
tube
feed
ings
or
TPN
indi
cate
d
Life
-thre
aten
ing
cons
eque
nces
D
eath
ALS
O C
ON
SID
ER: W
eigh
t los
s.
Asc
ites
(non
-mal
igna
nt)
Asc
ites
Asy
mpt
omat
ic
Sym
ptom
atic
, med
ical
in
terv
entio
n in
dica
ted
Sym
ptom
atic
, inv
asiv
e pr
oced
ure
indi
cate
d Li
fe-th
reat
enin
g co
nseq
uenc
es
Dea
th
REM
ARK: A
scite
s (n
on-m
alig
nant
) ref
ers
to d
ocum
ente
d no
n-m
alig
nant
asc
ites
or u
nkno
wn
etio
logy
, but
unl
ikel
y m
alig
nant
, and
incl
udes
chy
lous
asc
ites.
Col
itis
Col
itis
Asy
mpt
omat
ic, p
atho
logi
c or
radi
ogra
phic
find
ings
on
ly
Abd
omin
al p
ain;
muc
us
or b
lood
in s
tool
A
bdom
inal
pai
n, fe
ver,
chan
ge in
bow
el h
abits
w
ith il
eus;
per
itone
al
sign
s
Life
-thre
aten
ing
cons
eque
nces
(e.g
., pe
rfora
tion,
ble
edin
g,
isch
emia
, nec
rosi
s, to
xic
meg
acol
on)
Dea
th
ALS
O C
ON
SID
ER: H
emor
rhag
e, G
I – S
elec
t.
Con
stip
atio
n C
onst
ipat
ion
Occ
asio
nal o
r int
erm
itten
t sy
mpt
oms;
occ
asio
nal
use
of s
tool
sof
tene
rs,
laxa
tives
, die
tary
m
odifi
catio
n, o
r ene
ma
Per
sist
ent s
ympt
oms
with
re
gula
r use
of l
axat
ives
or
ene
mas
indi
cate
d
Sym
ptom
s in
terfe
ring
with
AD
L; o
bstip
atio
n w
ith m
anua
l eva
cuat
ion
indi
cate
d
Life
-thre
aten
ing
cons
eque
nces
(e.g
., ob
stru
ctio
n, to
xic
meg
acol
on)
Dea
th
ALS
O C
ON
SID
ER: I
leus
, GI (
func
tiona
l obs
truct
ion
of b
owel
, i.e
., ne
uroc
onst
