Response of osteosarcoma to preoperative intravenous high-dose methotrexate chemotherapy: CT evaluation.

Abstract

The histologic response of an osteosarcoma to preamputation high-dose methotrexate therapy can be used to determine the optimum maintenance chemotherapy regimen to be administered after amputation. This study evaluates computed tomography (CT) as a method of assessing the response of the tumor to the methotrexate therapy. Nine patients with nonmetastatic osteosarcoma of an extremity had a CT scan of the tumor at initial presentation. This was compared with a second CT scan after four courses of high-dose intravenous methotrexate. Each set of scans was evaluated for changes in bony destruction, soft-tissue mass, pattern of calcification, and extent of tumor involvement of the marrow cavity. These findings were correlated with the histologic response of the tumor as measured by the degree of tumor necrosis. The changes seen on CT correlated well with the degree of the histologic response in seven of the nine patients.

Full text

Page 1

89
Response
to Preoperative
High-Dose
Chemotherapy:
of Osteosarcoma
Intravenous
Methotrexate
CT Evaluation
JohnT. Mail1
D. Cohen1
Mirkin2
J. Provisor?
Mervyn
L. David
Arthur
Thehistologicresponse
be used
after
of assessing
nonmetastatic
presentation.
intravenous
destruction,
of the marrow
tumor as measured
correlatedwell
of an osteosarcoma
to determine
amputation.
theresponse
osteosarcoma
Thiswascompared
methotrexate.
soft-tissue mass,
cavity.These
by the
withthe degree
to preamputation
maintenance
evaluates
to the
of an extremity
with
setof scans
of calcification,
werecorrelated
of tumornecrosis.
response
high-dose
chemotherapy
computed
methotrexate
hada CT
CT scan
was evaluated
and extent
with the
The
in seven
methotrex-
regimen
ate therapy
to be administered
as a method
patients
at initial
high-dose
bony
ment
of the
canthe optimum
This study
of the tumor
tomography
therapy.
scan
afterfour
for changes
of tumor
histologic
changes
of the nine
(CT)
Nine
tumorwithof the
courses
a second
of
in Each
pattern
findings
degree
of the histologic
involve-
response
seen
patients.
on CT
Advances
patient
obtained
chemotherapy
therapy
in the plain
ing intensive
have
chemotherapy
correlated
specimen.
in the
over
therapy
the
patients
is based
high-dose
film and angiographic
chemotherapy
reported
areevaluated
withthe
of
15 years
for whom
on the
methotrexate
primaryosteosarcoma
[i -7].
the selection
histologic
and
appearance
via both intravenous
[1 0, i 1 ]. In our
by computed
histologicresponse
have
results
markedly
reported
improved
have
maintenance
to preamputation
[8, 9]. Changes
in patients
intraarterial
undergoing
These findings
in the
survival
in those
pastThe best
of postamputation
of the
additional
ofosteosarcomas
and
changesin osteosarcomas
tomography
of thetumor
been
response
various
tumor
agentswith
undergo-
routesselective
been study,
(CT).
seen
are
asamputated
Materialsand Subjects
Received
16, 1984.
April26, 1984: acceptedafterrevision
July
Presented
Society
1984.
I Department
ley Hospital for Children,
Center, 702
Address reprint
2 Department
ley Hospital for Children,
Center, Indianapolis,
in part
Pediatric
at the annual
Radiology,
meeting
Las
of the
AprilforVegas.
of Radiology,James Whitcomb
Indiana University
Dr. , Indianapolis,
requeststo J. T. Mail.
of Pathology,James Whitcomb
Indiana University
IN 46223.
of Pediatrics,James Whitcomb
for Children, Indiana University
Indianapolis, IN 46223.
Ri-
Medical
IN 46223.
Barnhill
Ri-
Medical
3 Department
ley Hospital
Center,
Ri-
Medical
AJR
0361-803X/85/1441
© American
144:89-93,January
1985
-0089
Ray Society
Roentgen
FromMay
were
1980
treated
to March
under
1983,
preoperative
nine patientswithnonmetastatic
incorporating
osteosarcoma
high-dose
were included.
proximal tibia,
patientshad their
The rest of the patients
but not yet confirmed
included chestradiographs,
entry into the preoperative
in each patient.
underwentan initial CT scan of the affected
contiguousscanswere obtainedfrom the adjacent
to a level where the marrowcavity became
extremity as a guide.Thus,in this retrospective
examined.Potential“skip”metastasesin the affected
were not specifically sought.
After confirmation of the diagnosisof osteosarcoma
an intensivechemotherapyregimen to be completed
of an
extremity
Four boys and five girls with a mean age of 12.8 years (range,
patients,thelesionswere located
patient’s tumorlocatedin the proximal
bone
biopsy performedat their referring
RileyHospitalfor Childrenwith
workup to excludemetastaticdisease
bone
scanning.As required before
studies were negative
Each patient
tumor,
tumor
protocolsmethotrexate.
5-17) In eight
the other
diagnostic
in thedistal
humerus.
institutions.
femur or the with
Fourinitial
were referred
A diagnostic
CT, and radionuclide
protocol,
to
suspectedosteosarcoma.
chest
chemotherapy these
extremity.
knee or shoulder
in appearance,
the entire
bone located
To evaluatethe primary
joint through
using the contralateral
bone was not necessarily
far fromthe primary
the
normal
study,
tumor
at openbiopsy,each patient
All patients
began
receivedbefore amputation.

Page 2

TABLE1: PreamputationChemotherapyProtocols
CN
ase
o.
Agent(s)
Administered
1
2
3
4
5
High-dose
High-dose
High-dose
High-dose
High-dose
vincristine,
High-dose
vincnstine
High-dose
vincristine,
High-dose
vincristine,
High-dose
vincristine,
methotrexate
methotrexate
methotrexate
methotrexate
methotrexate,
BCD
methotrexate,
6
7
methotrexate,
BCD
methotrexate,
BCD
methotrexate,
BCD
8
9
Note.-BCD
=
bleomycin,cyclophosphaimde,and actinoniyonD
TABLE
Chemotherapy
2:
Criteriaof GradedCT Response to Preamputation
Grade
of CT Response
cntena
1 , Poor response Increased
creased
creased
mality
No significant
Some decrease
some increase
Marked
marked
central
tent of marrow
bony destruction;
soft-tissue
extent of marrow
in-
in-
abnor-
mass;
2, No change
3, Moderateresponse
4, Excellentresponse
interval
in soft-tissue
in calcification
decrease in soft-tissue
increase
calcification;
abnormality
change
mass;
mass;
or
ex-
in peripheral
decreased
TABLE
Chemotherapy
3:
Criteriaof HistologicResponse to Preamputation
Grade of HistologicResponsecriteria
I
II
No effect
5%-95%
maining
Scattered
less than 5% of tumor
maining
No viabletumor
sampling
identified
of viabletumor cells re-
III foci of viabletumor
cells
cells;
re-
IV
.
cells
in extensive
gree
chemotherapy
specimen
Recent
histologic
onplain
demonstrates
chemotherapy,
wellwith
All patients
demonstrable
increased
oftheresponse
is the extent
in comparison
authors
response
radiography
that
the
the corresponding
with
progression
volume
of osteosarcoma
of necrosis
withthe
shown
of osteosarcomas
[1 0] and
in osteosarcomas
changes
histologic
gradeI histologic
of disease
of soft-tissue
to preamputation
in the amputated
biopsy
correlation
andthe changes
angiography
undergoing
demonstrated
response
responses
by CT,
massandprogressive
seen
initial[8,9,12].
the
seen
study
have goodbetween
[1 1 ]. Our
intensive
correlate byCT
of the tumor.
showed
primarily
easily
with
bony
90
MAILETAL.
AJR:144,January 1985
four courses
citrovorum
under more recent protocols
and the combination
mycinD (BCD).
of each patient.
At the completion
underwenta second
same
fashion
retrospectively
CT scans were evaluated
mass, patterns
by the primary
with the postchemotherapy
evaluated. These
the criteriaoutlined
individualevaluations
The degree
by examination
variousparts
withthe initial
by Huvos(Rosen
graded using
of intravenous
factor rescue over a period of 4-6 weeks.
were given additional
of bleomycin,
Table1 liststhe preoperative
high-dosemethotrexate (8-1 2 g/m2) with
Patients
agents: vincristine
and actino-
chemotherapy
treated
cyclophosphamide,
regimen
of preamputation
CT examination
described
by the two
chemotherapy,
of the affected
These
authors
eachpatient
in the
reviewed
extremity
wereasabove. studies
(J. T. M. and M. D. C.).
volumeof soft-tissue
of marrow
the prechemotherapy
the response of the tumor
were gradedon a scale of 1 to 4 using
2. A consensus grade
radiologist
for bony destruction,
and the extent
By comparing
studies,
responses
in table
differed.
of the histologic
of multiple microscopic
of the amputated
diagnostic biopsy.
et al. [8, 9, 12]),
criteriaoutlined
of calcification,
tumor.
involvement
studies
was
was assignedif
responseof the tumor
sections
Comparison
similar
the degree
in table 3.
was evaluated
of the tumor
was
to that developed
of tumornecrosis
from
madespecimen.
In a manner
was
Results
Representative
CT examinations
the results
andthe
Of the four
operative
showed
otherpatient
of tumor.
to chemotherapy
moderate
strated
histologic
ease on CT.
examples
are shown
ofpre- andpostchemotherapy
1-4. Table
the graded
tumor.
histologicresponse
(histologic grade
of progression of disease
in this group demonstrated
Of thefivepatientswith
(histologicgrade
or excellentresponseon CT.
no significantchange. None
responseshowed evidence
in figures
between
for each
poor
4 shows
of the correlation
histologic
patients
chemotherapy
definite
CT response
response
withto pre-
threeIor II),
signson CT.
regression
response
showed
patient
patients
of progression
The
moderate
histologic good
Ill or IV), foureither
demon-
with
of dis-
One
of the
good
Discussion
Figure5 shows the schema
currently
of nonmetastatic
Groupprotocol
of the primary
is usedto determine
regimen.Those
apy aremaintained
and can be expected
to potentially more
respondsatisfactorily
additionalrisks
the increasedyield
patients whoare
disease.Rosen et al. [9] reported
in a group of patients
The currently
for induction
investigation
and
at this
maintenance
institution
(Childrens
degree
chemother-
chemotherapy
for the
Cancer
response
apy
under
treatment
Study
osteosarcoma
CCG-782).
to preamputation
optimum
respond
sameagents
goodsurvival
agents. In those
preamputation
with cis-platinum
in disease-free
otherwisemore
Theof the
tumor
the
who
these
to have
toxic
to
of therapy
maintenance
well to induction
after
without
patients
chemotherapy,
are
survival
likely to
a 93% disease-free
a similarprotocol.
criterionfor
therapy
patients ther-
onamputation
exposure
whodo not
the
by
of
of
justified
group
relapse
in this
have
survival
undergoing
establisheddeterminingthede-

Page 3

Fig. 1 -Case
in soft-tissue
2. Proximal
and increased
humerallesion
destruction.
demonstratedgradeI histologicresponse.A, PrechemotherapyCT scan. B, Postchemotherapyscan.
Marked increase
mass
bony
Grade 1 CT response.
Fig. 2.-Case
in soft-tissue
8. Distal
Grade
femoral
3 CT response.
lesiondemonstratedgradeIV histologicresponse.A, PrechemotherapyCT scan.B, Postchemotherapyscan. Marked decrease
mass.
Fig. 3.-Case
in peripheral
6. Proximal
calcification
tibiallesiondemonstrated
in soft-tissue
gradeIII histologic
mass.
response.
4 CT response.
A, PrechemotherapyCT scan.B, Postchernotherapyscan. Markedincrease
rimlikeand decreaseGrade
AJR:144,January1985
CT RESPONSEOFOSTEOSARCOMATO CHEMOTHERAPY
91
destruction
involvement
were
did
not
Four
necrosis
moderate
(fig.
was
1).
also
poorly
significantly
Anincrease
in some
defined
with
who
IV histologic
changes
intheextentofmarrow
margins seen patients.
group
Tumor
of patients
somewhat
change
of the five patients
(grade
orexcellent
in this
chemotherapy.
showed
response)
by
and
good histologic
demonstrated
(grade
tumor
Ill or
CT3 or4 CT
response).
decrease
Chuang
chemotherapy
patterns:
mass
of the tumor.
The
in size
et al. [1 1]reported
demonstrated
dense rirnlike
diffusely
In our group
most
of the
consistent
soft-tissue
finding
mass
osteosarcomas
increased
calcification
increasedcalcification
of patients
in the group
(fig.2).
was the
thatundergoing
calcification
periphery
in the
showing
in two
of
part
at thethe
andcentral
histologic
good

Page 4

92MAILETAL.
AJR:144,January1985
Fig.
4.-Case7. Distal femoral
abnormality.
lesion demonstrated gradeII histologic response.A, Prechemotherapyscan.B, Postchemotherapyscan.
Decreasein size of
soft-tissueGrade 3 CT response.
INDUCTION MAiNTENANCE
HDMTXOFF
?
THERAPY
_________
VCR
ADR
BCD
BCD
=
BLEOMYC1N,CYCLOPHOSPHAM1DE.ACT1NOMYCiN-D
?CR
=
ViNCRISTINE
ADR
=
ADR1AMYC1N
HDMTX
=
HiGH-DOSEMETHOTREXATE
ciS
PT
=
C1S PLATINUM
Fig. 5.-Schema
osteosarcoma.
forinduction
Grade
for maintenance
CCG-782,
and
of
maintenance
histologic
chemotherapy
determines
(From
for non-
metastatic
chemotherapeutic
Study Group Protocol
responseoptimal
Cancer agentstherapy.
data.)
Childrens
unpublished
TABLE
Histologic
4: Correlation
Response
of GradedCT Response
withthe Graded
Graded HistologicResponse : Case No.GradedCT Response
1
2
1
1
.?
1
73
III:
64
IV:
3
5
8
9
3
4
3
2
response,
served
In these
of calcification,
to changes
mass
superior
make
criteria
angiography.
Changes
helpful
response.
thatthe
marrow
unless
poietic
detect
between
believe
accurate
In two
withthe
grade
CT demonstrated
of calcification
realms,
CT can
chemotherapy.
its relation
contrast
a more effective
thancan
analogous
(fig.
of soft-tissue
be expected
changesin the ob-
patterns 3).
twosizemassandpatterns
sensitiveto be especially
Better definition
facial
calcification,
examination
accomplished
from of soft-tissue
as well
permits
twoimportant
radiography
and to surrounding
resolution
planes, as
to for CT
of these
byplain be or
in the
evaluating
Most
abnormally
seen
the necrotic
or fatty
marrow
active
that
sign
patients,
histologic
II histologic
extentof marrow
patients
no significant
increased
chemotherapy
tumorwas
tissue.Despite
abnormality,
tumorand
persistence
of poor response
changes
response
response
involvement
showing
change.
attenuation
would
replaced
thesuperior
wereunable
necrotictissue.
of marrow
to chemotherapy.
identified by CT failed
of the tumor.
(anunsatisfactory
were
histologic
theorize
involved
not
inthe
good
showed We
theof
beforenot be normalized
by normal
ability
to differentiate
Hence,
abnormality
hemato-
of CTto
we
we do not
the
isan
to correlate
patient
response)
Onewith a
showed
4). This
soft-tissue
grade
significant
sclerotic
There
the pattern
minimal.
change.
Overall,
amputation
histologic
logic
thedetermination
based.
it has
changes
sponse
evidence
response
of moderate
was
regressionof tumor
as a decrease
demonstrated
necrosis) but
patient’s initial
cortexand
to monitor, and
in this alreadysclerotic
the extent of marrow
on CT (fig.
manifested
Another
response
on CT.
confined
no soft-tissue
of calcification
In addition,
primarily
patient
in
aabnormality.
IV histologic
change
tumor
was
(1 00% showed
showed
no
This
to the
mass
scan a
medullarycavity.
the change
tumor
in
was
abnormalitydid not
the
chemotherapy
response
response
CT-gradedresponse
correlated
of
remains
maintenance
replacement
clinically
illustrate
maybe of
of
with
thetumor
degree
topre-
theof the
histo-in seven
tumor
of optimum
advocate
to
CTdo
and
thenine patients.
standard
chemotherapy
of this
effective.
a moremacroscopic
benefitin evaluating
The
on whichof the the
is
We do not
been
seen
totherapy
standard,
However,
as
shown
on
bethe
re-
the

Page 5

AJR:144,January1985
CTRESPONSEOFOSTEOSARCOMATO CHEMOTHERAPY93
overall
Further
histologic
might
in maintenance
and noninvasive
response
treatments
methotrexate).
who do
could be altered
of induction
biologic
research
response
together
response
is needed
plus
better
chemotherapy
method,
to chemotherapy
(i.e.,after
It may
not
respond,
or amputation
therapy.
of the tumorto thechemotherapy.
if a combination
demonstrated
patientsin whom
is indicated.
CT mightbe used
earlierin the
oneor twocourses
possibletodetect
thatpreoperative
performed
to determine
response
those
of
thebyCT
definea change
effective
tumor
of induction
of high-dose
those
chemotherapy
at an earlier
As an
to monitor
course
only
bepatients
so
stage
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