Download Current Perspectives in Small Cell Lung Cancer

Current
Kenneth
Perspectives
R. Hande,
M.D.;t
in Small Cell Lung Cancer*
and
Roger
M. Des
Prez,
M.D.
()
ver the past three
decades,
concepts
concerning
small
cell lung cancer
(SCLC)
have undergone
major
changes.
In the 1950s,
SCLC
was treated
surgery
although
malignant
in the same
manner
it was
recognized
form and that the
generally
land,
son
poor.
which
impact
of
results
of
were
(to
had,
indicated
localized
growing
whether
chemotherapy
lung
tumor
than
cancers,
of local disease
the
unsatisfactory
by surgery
local
the
by
or
was
usually
usual
surgical
are cells
treatment
and radical
the metastatic
disease
which
present
became
established.
used,
with
The
were attributed
to the propensity
of
and
widespread
metastases.
Since
themselves
more
sensitive
to both
and
radiotherapy
than
poor.
the
with
rasurgery,
was
chemotherapy
assumed
Since
was
of lung
shown
hypothesis
than
quency
most
of brain
nervous
prophylactic
The major
tic approach
hypothesis
other
metastases,
system
cranial
For
for
SCLC
be
themselves
not
cancer
that
from
the
lung cancers
that
tumor
developed
were
several
of
etc) which
features.
share
4From the Vanderbilt
University
Veterans
Administration
Medical
certain
Center,
of Medicine,
tAssociate
Professor
of Medicine
and Pharmacology.
1:Professor
of Medicine.
Reprint
requests:
Dr Hands,
VA Medical
Center,
South,
Nashville
37203
the
The
chitsky
cell)
highly
Nashville
TN.
1310 24th Avenue
(Table
led
separate
It is clear that
with
“apudomas.”
patients
of
carof
1966 by
and
the
of
all derived
from
by the
common
of the
enzymes
decarboxylase
providing
property
of amine
precur(APUD).
The finding
of
“apudoma”
and
thyroid
in SCLC
1)
cells
to the
from
and
with
the associa-
this
particular
concept
of neural
behavior
this idea
from
part
and
bronchial
relatives
introduced
in
corticotrophs
the
B cells
production
to chemotherapy
strengthen
origin
concentrations
hormone
malignant
sensitivity
trations
enzymes
several
tissue
granules
all
from
which
be grouped
and dopamine
the biochemical
and decarboxylation
cells
and
of the
could
that
or K cells
the
pituitary,
C cells
and
was
that
of high
a malignant
to
concept
histaminase
them
with
sor uptake
was
believed
investigators
Kulchitsky
properties
from
and
Nashville.
crest
cancer
the
the
suggested
of the
and the
neural
taken
School
been
doubt
completeness
has been
exhaustive
recent
reviews
of neuroectodermal
APUD
lung
biochemical
now
APUD
system,
and that
similarly
derived
benign
The
therapeu-
the pulmonary
entoderm.
In this respect,
SCLC
was
thought
to be related
to other
endocrine
cancers
(medullary
carcinoma
of the thyroid,
pancreatic
islet
cell tumors,
morphologic
were
Pearse,3
who
melanotrophs
the
many
from
the so-called
cinoids
were
of ectopic
to derive
Many
some of these
controversies
and
attitudes
concerning
treatment.
years,
derived
tion
contrast
thought
to address
present
neurosecretory
from
in
the
centers.
and
support
neuroectoderm,
which
the fact
in many
in classification
received
strong
this
all cases
The fre-
do not penetrate
led to the practice
irradiation
differences
to SCLC
with
together
agents
well,
Various
have
HIS1DGENESIS
in a radiother-
disease,
comprising
that,
came into use.
chemotherapeutic
central
derived
extensive
than
therapy
tenable.
available.’2
pancreas,
apy port,
and
more
advanced
effective
chemotherapy
No attempt
at bibliographic
made,
as other
excellent
and
strable
be encompassed
never
promise.
and
The
SCLC
has an entirely
different
histoother
lung cancers.
It is the purpose
of
this review
to summarize
are
site
challenged.
that
genesis
SCLC.
could
is
radiation
disease
has been
and
some
of
completely
of surgery
to have
based
on anatomic
extent
of disease
was felt to be
inapplicable
to SCLC.
The simpler
classification
of
limited
disease,
indicating
cases
in which
all demondisease
primary
that
surgery
to be no longer
of
to always
surgery
classification
the
concerning
of the 1970s,
usefulness
to the brain
of more
strategy
The
to
combinations
the
these
concepts
the orthodoxy
questioned.
both
appears
in comparithat
been
contention
in Eng-
disease
better
quite
which
responsive)
to early
cells
are
radiation
it has
local treatment,
radiotherapy
slowly
small
have
many
of
constituted
prophylactically
were
study
quite
slightly
both
of surgery
a clinical
present,
which
therapy
lung
cancers,
was the
most
was
of
were
although
quite
SCLC
SCLC
that
treatment
diotherapy
results
1960s,
in retrospect
to the
results
In the
as other
that
it
by
At
SCLC,
that
crest
other
cell
lung
of SCLC and
and irradiation
of a separate
SCLC
(Kul-
origin
cancers.9
its greater
helped
cell of origin.
to
SCLC
has many properties
associated
Plasma
and tumor
tissue
samples
with
SCLC
have
elevated
concen-
of histaminase
and
L-dopa
decarboxylase,
associated
with
APUD
cells.’#{176}” However,
lines
of evidence
now
indicate
that
SCLC
derives
from the
sor as other lung
same pulmonary
entodermal
precurcancers
and differs
only in its degree
CHEST
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/ 85
/ 5 / MAY,
1984
669
Table
1-Ectopw
Hormone
Production
Cancer’
Elevated
Clinical
Levels
common
At
Plasma
Hormone
Cell Lung
in Small
Symptoms
Hormone
%
Of
Production
%
than
that
all
related
many
lung
entoderm
that
direction
change
1-11
ACTH
11-40
1-5
Calcitonin
38-65
.
cytotoxic
therapy.’2’3
Neurophysins
42-62
.
proposed
a “Y”
of
differentiation.’2”
based
on biochemical
weakened
also
by the fact
demonstrate
hormones,
Yesner
and
scopic
although
bridges
mucin
can
both
and
at the
time
of initial
of
As
as
origin.
will,
of other
cell
types.
many
at autopsy,
types
These
‘3-’
and
derived
the
latter
does
much
crine
et al’2 have
believe
that
K cells
that
the
cell
of treated
admixtures
entirely
to other
suggest
that
cell
demonstrated
lines
large
and
not comport
cell
the
cell
lung
that
SCLCs
are
with
are
are
not,
are
and
that
of the
carcinoids
since
more
Yesner
relatives
the fact that
SCLC,
mor-
carcinoids
benign
in most
rather
are
endo-
than
ment implications.
has been
given
variant
of SCLC,
from
large
the
less
LARGE
CELL
UNDI FFERENTIATED
CARCINOMA
prognosis
ion that
weakened
FIG
USE
cancers
(Adapted
670
CELL
(Oat
Cell
and
of the
these
degree
Carter
RELIABILITY
large
cell un1). This unitary
and
removes,
problems
with
polygonal
subtype
The
(WHO)
1967
and
histologic
sented
into
in Table
oat
types.
The 1981
variants
fusiforin
1967
of
that
is better
and
combinations
of
are included
combinations
SCLC
would
be
between
is the
IDENTIFICATION
OF
Health
of
scheme’7
fusiform,
Organization
SCLC
are presubdivided
SCLC
and “other”
sub-
the
polygonal
and
the
and introduced
comprising
tumors
containother
histologic
types.
Tumor
with
large
cell lung
carcinoma
under
the intennediate
designation
of SCLC
with
squamous
cell
are
unopin-
classified
while
and/or
as combined.
that the various
SCLC
have
different
responses
to therapy,’’
others
have indicated
that they do not. ,23 The
Some
studies
have
suggested
ability
of pathologists
and its morphologic
such
The unitary
regard
the
more
differ-
as operable
scheme’8
grouped
as intermediate,
new category
of combined
ing SCLC
together
with
different
suggestive
contend
SUBTYPES
1981 World
classifications
polygonal,
thought
polygonal
in SCLC
difference
regarded
AND
2. The
cell,
by
treat-
towards
large-cell
the widely
held
HIs’rowGIc
OF
have
relationship
shows features
tumors.
Some
and other
cancers
of differentiation.
can
including
and
the
surgery
is never
indicated
somewhat
if the only
distinctions.
to consistently
identify
SCLC
subtypes
is obviously
critical
to
A recent
2-Histopathologw
Carcinoma
study
by
Clausfication
of the Lung8
Hirsch
et
of Small
Cell
al
of SCLC)
WHO
SMALL
Yesner
describing
entiated
tumors
on their
way
differentiated
histology.
Finally,
Table
Varients
influences
attraction
classification
the oat cell type
cell undifferentiated
subtypes
whereas
Polygonal
Drs.
usually
tumors,
others
that it is worse than oat-cell
tumors.
theory
of lung cancer
histogenesis
would
polygonal
subtypes
of SCLC
as slightly
CARCINOMA
I (?
histology,
For instance,
considerable
as to how to classify
the
which
is morphologically
adenocarcinoma
ADENOCARCINOMA
of
concept
great
some
pulmonary
differentiated
a variety
SCLC
in vitro
lines
cancer.
bronchial
former
less frequent
than
organs,
adenomas
to
concept
has
simplification,
SCLC
exposure
to cytotoxic
therapy
and more
chemotherapy-susdifferentiated
and less suscepticell
from
notion
frequently,
either
findings
SCLC
resembling
Carter’3
found
for a common
of cases
or conversion
of
phologically
types
or, more
percent
autopsy
Gazdar
conversion
tumor
strongly
25
actu-
homogeneous
demonstrate
evolves
during
clinical
from less differentiated
ceptible
cells to more
ble cells.
mixed
diagnosis
argues
(squamous
superficially
of
or death,
cell type,
carcinoids),
(adenocarcinomas)
in
at relapse
SCLC
features
tonofilaments
production
and
degree.’#{176}’4
light
micro-
morphologic
all be found
The
presence
tumors.
D enzymes
diagnostic
of one or another
core granules
(SCLCs
and
intracellular
ally
features
is greatly
cell lung cancers
ultrastructural
thought
to be
such as dense
and
of separateness
hormonal
non-small
to a much
smaller
contend
that
both
Carter’3
and
cell),
argument
and
that
APU
by
in specific
more
believe
from
between
various
lung
cancers
with
differentiated
cancers
at the fbrk (Fig
The
characteristic
produced
investigators
are derived
of the
28-41
be
carcinomas.
prominent
cancers
and
in the
ADH
the
present
CARCINOMA
Type)
1. Histological
flow of lung cancers
indicating
that all lung
are part
of a spectrum
of differentiation
that
is mobile.
from Yesner
and Carter. 13)
1967
WHO
1981
1. Fusifurm
1. Oat-cell
2.
Polygonal
2.
Intermediate
3.
Uymphocyte-like
3.
Combined
4.
Others
(oat-cell)
cell
Small Cell Lung Cancer
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small
carcinoma
(Hande,
Des Fez)
specffically
addressed
pathologists
were
fication
of
this
able
SCLC
classifications
issue.
using
pathologic
of the
of
time
and
the
was
found
WHO
“minimally
only
1967 classffication
the
more
histo38
and
54 percent
of cases using
the 1981 classification.
This
indicates
that an experienced
pathologist
can
identify
SCLC
in the majority
of cases
al-
study
reliably
though
5 to 8 percent
However,
from
group
subtyping
investigator
of mixed
accurate
of SCLC
PROGNOSTIC
two
most
critical
of disease
TNM
status.
The
is very
useful
less so
patients
AND
not
for other
types
and
patients
poor due
tastases.’9
to a high
Therefore,
two-stage
classification
frequency
most
more
to
disease
study,
praclavicular
pleural
some
nodes
which
cancer,
is much
85 percent
at the time
of SCLC
of initial
prognosis
of stage
been
VA Lung
than
that.
have
varied
su-
includes
However,
defini-
somewhat
from
contralateral
including
studies
bone
consists
marrow
su-
malignant
(positive
nuclide
in most
chest
recent
x-ray,
identical
pleural
and radio(positive
in
effusions
studies
ance
status
independent
have
Patients
limited
have
on
omitted
times,
scanning
presentation.
some
However,
of these
some
staging
more
extensive
examinations
and
peritoneoscopy
have
Early
studies
using
the median
survival
few staging
of untreated
investigators
procedures,
and
at
including
CAT
been
included.
procedures
patients
measured
with limited
Other
previous
surgery,
been
consistently
appropriate
controls
factors
As previously
perform-
do less well
have
those
as
with
age,
and
shown
than
of disease.
generally
such
is
is an important
treatment
re-
a better
extensive
sex,
histologic
to have
immune
subtype
prognostic
IN
mentioned,
SCLC
untreated
patients
subgroup
of patients,
the median
weeks,
and fewer than 5 percent
late 1960s,
agents
In the
improved
to such
have
next
and
an extent
the
demonstrated
activity.
in SCLC
the International
Cancer
(IASLC).
decade,
results
that
therapy
chemotherapy,
three
and
is
require
current
the
drug
status
dependent
on certain
single
than
dosage
prognostic
CHEST/85/5/MAY,1984
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by
Study
of Lung
concluded
that
agent
two,
and
sufficient
a certain
degree
of serious
toxicity
fall in hematologic
parameters
in some,
and some
deaths.
Results
to be
of
reviewed
to
better
A
of drugs
recently
preferable
are
chemofor SCLC.
combinations
1.2.42 The
that
in
combinatreatment
combination
has been
drugs
was only 43
were alive
new drug
of drug
of therapy
Association
for
This
committee
multiple-drug
results
survival
of patients
six
re-
that
surgery
in this
it was demonstrated
improved
survival
mainstay
drugs
with
survival
of only
little
to overall
sults.u
Studies
in the early
1960s4#{176}
demonstrated
radiation
therapy
was slightly
better
than
when
used
in limited-stage
disease.
Even
maximal
for
prognosis
a patient’s
small cell lung cancer
have a median
to 17 weeks,3#{176}and surgery
adds
noted
totally
and in
Hepatic
sign,
but
import.
figures
be
overall
site
the
of stage
than
disease.
stage SCLC
at three months
and the median
survival
of
patients
with extensive
disease
at 1.5 months.3#{176}These
not
that
patients
status
function,
have not
produce
predictable
infection
may
shown
stage
chemotherapy
limited
that
response
extensive
The
2.31
worsen
regardless
perfbrmance
dures,
disease
therapy.
are not ambulatory
who
patients
of individual
have
improv-
demonstrated
at the time
of diagnosis
variable
in determining
number
will
limited
not
have
higher
those
with
do not generally
20 to 35 percent,
and 20 to 40 percent
of patients,
respectively).
2.31 Using
these
tests
as screening
procepatients
both
while
those patients
who otherwise
have limited
disease.”
The data on isolated
brain or bone marrow
metastasis
is now
of all SCLC
disease
of
therapy
one-third
have
SCLC.4’
During
the
tions were
developed,
of physical
examination
in 10 to 45 percent
of patients)
scans of the liver, brain,
and bone
of studies
more
extensive
within
better
receiving
Hansen,’5
tumor
bulk
both
at the primary
disease
metastatic
lbci also
influences
prognosis.’5
involvement
appears
to be a bad prognostic
at five years.
chemotherapeutic
effusions.
Staging
examination,
results
groups
CHEMOTHERAPY
without
3#{176}
soine
disease
and
in classifying
as
patients
with
limited
disease
rates
and survive
longer
than
Cancer
ipsilateral
disease
including
and
or
results.
number
by Ihde
result
patients
to make
overall
However,
as limited
is defined
as
with
out
will
disease
A large
initial
1
as
regarded
patients
disease
appear
ambulatory
of undetected
micromestudies
have employed
the
of the
extensive
sults.
of lung
scheme
advanced
of limited
are
performance
system,’5
the surgical
has generally
thus
and
ing
staging
extensive”
conflicting.
Several
staging
tumor
confined
to one hemithorax
local
extension
and with
or without
praclavicular
nodes,
while
extensive
study
in the
cell in
in SCLC
patient’s
Group
which
categorizes
and extensive
stage.
Limited
tions
consistent
MANEUVERS
factors
the
cancer
Further,
all cases
be
STAGING
in SCLC.
More
than
have
stage
3 disease
2 SCLC
misclassified.
for SCLC.’827
prognostic
and
lung
presentation.
Study
stage
may
examination
FACTORS
stage
be
some
features
of large
cell cancers.’5
cytologic
examination
appears
to be as
as histologic
The
may
to investigator,
particularly
tumors
predominantly
small
type but having
Parenthetically,
the
of cases
extensive
and
in
As pointed
studies.
classi-
of tissues,
on
SCLC
using
1981
94 percent
today’s
lung
general
agreement
subtyping
percent
1967
and
However,
expert
on the
the
in 91 percent
respectively.
Three
to agree
to
with
a
in all,
were
features
671
as
discussed
above.
compiled
by the
3. The
The
“State
IASLC
authors
of the
group
are
that
the end-point
very
useful,
and
measurement
of any regimen’s
efficacy
two or preferably
three
years.
Results
survival
felt
time”
presented
mens.
is
in
3 will
little
identify
suboptimal
produce
results
regi-
drug
regimens4
similar
those
outlined
in Table
3 with
no one
showing
marked
superiority
to others.
incidence
of significant
toxicity
2 to 5 percent,
is regarded
above,
a necessary
feature
Some
toxicities
are related
most
frequent
lethal
neurotoxicity
with doxorubicin,
problem
episodes
in
30
with
percent
treated
patients.
Infection
can be demonstrated
to 40 percent
of patients
with white blood counts
1000/cu
ent,
mm.
coccus
half of these,
In
most
often
aureus,
due
to
bacteremia
Pseudomonas,
coli,
or Klebsiella
Prophylactic
antibiotic
treatment
patients
including
gastrointestinal
with
aminoglycosides
useful
marked
trum
and
antibiotics
not
rapid
at the
to be
with
of fever
broad-spec-
has
minimized
mortality.5’
The good results
with multiple
drug chemotherapy
achieved
during
the early 1970s have not been substantially improved
upon in spite of numerous
variations
in
drugs,
dosage,
agents.
high-dose
In
resistant
particulai
chemotherapy,
drug
improved
Table
scheduling,
use
have
results
of the Art
introduction
of new
of four-drug
combinations,
and alternating
non-cross-
combinations
treatment
3-State
and
to date.
Reeults
of
not
Administra-
1.2.46.32.33
Chemotherapy
Limited
Extensive
Stage
Stage
Patients
Patients
definition
of SCLC
All
Patients
the
to
(CR)*
Partial
response
rate
(PR)
CR
Bate
Median
survival
(mo)
to the
diagnosis.’6
radiotherapy
3-Year
survival
patients
given
percent
of
*Complete
partial
one
672
response
response
month.
5%-10%
is disappearance
is 50 percent
Adapted
from
of all measurable
or greater
Aisner
shrinkage
et al.43
lasting
disease
and
for at least
TREATMENT
stage”
SCLC
OF
as cases
in which
all
by a single
raimportance
initially
in
treatment.
The
effective
than
surgery
stage
SCLC,
gave
importance
early
Council
radiation
alone
early
fur
em-
of radiotherapy.4#{176}
port by chemotherapy
effect on the primary
of patients
with
(2) Chemotherapy
chemotherapy
patients
and
combined-modality
survival
results
0
THE
A
rather
tumor.
By
concluded
that
of chemotherat the time
of
disease
confined
alone
is less
effective
in controlling
intrathoracic
disease
than the
combination
of chemotherapy
and radiation
therapy.
Relapses
in the chest
occur
in roughly
50 percent
of
information
15%-20%
may
after
treatment
of limited-stage
SCLC.
An excellent
recent
review
by Cohen3#{176}draws
the following
conclusions:
(1)
Both radiation
therapy
and chemotherapy
alone
can
40%
12
this
early
At present,
it is by no means
certain
that
is in fact additive
to chemotherapy
in the
50%
75%
a
Also,
of
that
relapse
the late 1970s,
most investigators
had
radiotherapy
did not add to the efficacy
apy in disease
which
was extensive
30%
7
suggest
who
of limited
beyond
the radiotherapy
than to any synergistic
therapy
toxicity
radiation
75%
lasting
was more
potential
35%
14
re-
later
BMRC
study
demonstrated
that
combination
radiotherapy-chemotherapy
was more
effective
than
radiotherapy
alone,3#{176}attributing
this to control
of foci
25%
80%
IN
radiotherapy
treatment
50%
+ PR
“salvage
the
British
Medical
Research
mentioned
above,
indicating
that
chemotherapy
Complete
response
rate
with
remission
platinum
of “limited
cure a small number
to one hemithorax.
significantly
have
by retreatment.’5
the
combination
known
tumor
can be encompassed
diotherapy
port
indicates
the
phasis
of the
care-
a second
for those
RADIATION
alone
species.4746
of
who
therapy.’657
therapy
yb-
plus
regimen
THORACIC
The
study,
(VP-16)
be an active
by
be pres-
chemotherapy
may be produced
studies
using
studies
(BMRC),
Staph
has also proved
of patients
initial
recent
attributed
is thought
treatment
to one
year or longer
preliminary
of
by others.’#{176} In spite
seen in most patients,
onset
following
in 20
under
of granulocytopenic
decontamination
or cotrimoxazole
by some49 but
granulocytopenia
ful observation
will
Escherichia
as
chemotherapy
Retreatment
regimens”
has, fur the most part, produced
disappointing results
(less than 30 percent
PR rate). An exception
to this rule may be “late relapsers”
(relapse
over two
years after initial
remission)
in some of whom,
accord-
standard
with
but
is neutropenia
occur
value.54
etoposide
in
as usual,
and, as mentioned
of adequate
drug regimens.
to specific
drugs,
such
serious
Febrile
combination
An overall
in 25 percent,
renal
disease
with
platinum,
vincristine,
and cardiac
toxicity
infection.
to
of “maintenance”
lapsed
ing
Several
the
tion
of “median
that the best
is survival
at
poorer
than
not
Table
results
in Table
Art”
presented
only
treated
radiation
and
with
in
only
25
a combination
therapy.
61.62
of
(3) Chemo-
alone,
in general,
has less acute
and chronic
than
the combination
of chemotherapy
and
therapy.
As Cohen
states
“from
the above
it
might
intuitively
treatment
in limited-stage
be
concluded
that
would produce
superior
SCLC
patients
(be-
cause
of increased
local control)
at a cost of increased
treatment-related
morbidity
and mortality.
Unfortunately
these
assumptions
are not conclusively
borne
out
by clinical
In
trial
nonrandomized
results.”
trials,
the
complete
Small Cell Lung Cancer
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21409/ on 05/05/2017
response
(Hande,
Des nez)
and median
rate
comparable
survival
to
and radiation
dressing
this
with
those
with
therapy.2
question
in these
no improvement
to chemotherapy
favored
combined
results
ences
in radiation
Cox3#{176}
contend
that
may
dosage
fewer
and
than
chemotherapy
is inadequate.
ation
should
chemotherapy
be administered
rather
than
results
alone
are
transient,
chemotherapy
Several
randomized
have been
reported
form. Two have shown
therapy
as compared
others3#{176}’46
have slightly
difference
chemotherapy
combined
well
trials adin abstract
with combined
alone;3354
two
therapy.
The
be
due
schedule.
Others
abnormalities
to differ-
believe
that
simultaneously
sequentially
for
The
most
radi-
trials
with
maximal
in increasing
ously
initial
mentioned,
intrathoracic
importance
argument
for the combined
chemotherapy
effect
the
in SCLC
number
published
local
control
in
in
treatment
treated
percent)
(radiation
plus chemotherapy)
than in those
with
chemotherapy
alone
(17 percent
vs 7
when
nonrandomized
studies
are compared.’
preliminary
indicate
that
three years
combined
the
with
results
combined
pais
of
percentage
modality
randomized
of patients
trials
alive
to
in
following
diagnosis
chemotherapy-radiation
is significantly
therapy
higher
treatment
groups
than in those receiving
A recent
review
of this issue
chemotherapy
by the IASLC
alone.
concludes,
“No
advantage
been
shown
suggest
in
short-term
a possible
loco-regional
studies,
advantage
advantage
will be
once
the
in long-term
demonstrated
optimal
dosage
but
in long-term
disease.”3#{176} It is the
some
SCLC
worked
(median)
in randomized
and
IN
Ten
percent
system
and
during
SCLC
effective
the
patients
to 80 percent
will
(CNS)
20 to 50 percent
course
more
develop
in preventing
ingly, prophylactic
widespread
use
era.
Usually
Complications
therapy,
brain
CNS
cranial
quite early
2,500
are,
have
a
at the
time
of
reserved
it
Of
survival,
documented,
six months
two years,
do not cross
do have been
metastases.5266
are
part,
the
in-
Accord-
irradiation
(PCI) came
in the SCLC chemotherapy
to 3,000
rads
for the most
60
Most
The
administered.
minimal
a strong
cranial
irradiation
on the
very
survival
into
and
with
administered
usually
two
after initiation
CNS
as
The
from
percent
in
contrast
to
and improved
percent
to 38
some
metastases
incidence
0.5 percent
surviving
thereafter.
Its development
with
recurrence
of disease
(spinal
are
being
survive
of prolonged
CR has been
but less than
cord
lesions
or
observed
more
for appreciable
of carcinomatous
meningitis
at the time of diagnosis
to 25
three
years,
plateauing
is almost
always
associated
elsewhere,
often
an inCHEST
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21409/ on 05/05/2017
hope
only after
to four months
of treatment.
meningitis)
more
patients
those
achieved
of CNS
to a comparable
group
not given
a strong
argument
that PCI be
and
periods.74
increases
be expected
In
in patients
who
the incidence
reduced
for CR patients
Extracranial
until
to chemo-
can
3).
argu-
important
response
(Table
use of PCI
response
carcinomatous
frequently
and
taken
as a whole,
17 percent
of CNS
most favorable
group were single organ
percent
compared
PCI. This
provides
will
metastases.66’7#{176}
prolonged
is so
isolated
in those
with more
and in those in whom
complete
percentage
patients
in this
not
is not achieved,
for deferring
with
in whom
only
rest of
metastases
usually
metastasis
from 52 percent
to 25 percent
the
two-year
survival
rate
from
16
disease.31’66
than
(CR)
in a reasonable
(PCI)
will develop
of their
surviving
in the treatment
of SCLC
barrier,
and those which
drugs
used
blood-brain
response
of patients
Moreover,
when
they
headache
for the
ofCNS
are
has
are
since patients
also develop
and this will be the
treatment
these
data
SCLC
metastasis
nervous
diagnosis,
Since
since
can be made
frePCI
(65 to 90 percent)
of all patients
regardless
of the severity
of
therefore
not critical
for survival
than limited
disease
at the outset
metastasis.
SCLC
irradiation,
majority
metastases
and
details
with
initial
those
cranial
SCLC
relapses
of all patients
central
sometime
lives
in the
CNS
symptoms.66’72
et al.46
are really quite good, especially
are early and minimal.
All patients
their
after
a
been
in the
survival,
will usually
survival
of
have
receiving
case
with
control
in limited
stage
with combined
therapy
IRRADIATION
in median
metastases
current
that
low and
role is still
randomized
in patients
are associated
with
of neurologic
symptoms
group
to be
by Bleehen
whose
metastases
will remain
free
complete
CRANIAL
metastasis
evi-
on CAT
reduction
CNS symptoms
develop.
A recent
study73 has focused
of scheduling
some
noted
in SCLC
summarized
symptomatic
symptoms
complete
out.
PROPHYLACTIC
of PCI
ment
opinion
although
sound,
its proper
At least
seven
65.66
control
authors’
changes
disease
at other metastatic
sites.
of treatment
of CNS metastases
effective
two
dysarthria,
loss,
combination
have been
of SCLC patients
who
no significant
clinical
a significant
of CNS
become
so when
long-term
SCLC
diagnosis
memory
effect
demonstrate
progressive
the results
the
the
greater
Similarly,
treated
at
the
but no improvement
who develop
CNS
As previ-
achieving
survival.
The percentage
of limited-stage
tients
free of disease
two years after initial
patients
use
occurs
emphasizing
EEG
as recently
Most
is its apparent
of “cures.”
relapse
frequently
site of disease,
of
studying
quency
persuasive
with
or
the rationale
fur its use
matter
of disagreement.
to be obtained.
of radiation
minor
dence
of mild cerebral
atrophy
has been
scanning
of the brain
in over half.7’
Although
the toxicity
of PCI appears
Byhardt
and
given prior to
4,000 rads
although
tremor,
and myoclonus
in some
reported.46
Long-term
fbllow-up
have
received
PCI has shown
/
85 I 5 I
MAY, 1984
673
tracranial
metastasis.
achieved
with
maximal
but
Limited
involvement
such
palliation
a combination
plus
treatment
has
of radiation
intrathecal
has been
been
to the
histologic
site
mors,
or in tumors
cinoids,’#{176}an assertion
of
presuppositions
is very likely,
methotrexate,
of little
benefit
in terms
survival,
SURGERY
For
many
treatment
years,
the
of SCLC
of this
cell
type
operation.
disease
attitude
was
was
SCLC
IN
toward
so negative
considered
The
depressingly
present
at time
the
that
demonstration
usual
finding
of metastatic
present
lung
there
cancers).
is good
In 1975,
extensive
with
Higgins
Veterans
solitary
SCLC
cases
which
Shields
I or II
these
the
with
SCLC,
survived
the operation.
The
these patients
was 23 percent,
(Table
4). All received
some
chemotherapy
but
day standards.
Essentially
been
by Shore
and
with
148 of
132 of these
five-year
survivorship
in
all in early stage patients
single-agent
adjunctive
in insignificant
amounts
similar
and
results
Paneth.7’1
by present
have
recently
Of roughly
was
authors
used
in
indicate
the
Bromptom
that they
now
would
use chemotherapy.
These
results
indicate
a place for surgical
resection
in the unusual
patient
with SCLC
who presents
with
stage
1 or 2 disease.
Some
good
surgical
in
results
Table
Total
cancer
Results
4-Surgical
resections
reports
SCLC
for cure
SCLC
cases
resected
for cure
SCLC
cases
surviving
30 days
Stage
1
contend
are
in the
that
polygonal
in SCLC5
148
op
132
5-Year
survival
59.5%
T, N,
M,
31.3%
T, N,
M0
27.9%
2
T,N,M0
Stage
9.0%
3
T,orN,
9Adapted
674
3.6%
from
Shields,
et al.1’
adjunctive
multiple
to
preliminary
multiple
drug
drug
such
from
(four
cure,
T2-N,,
eight
chemotherapy
chemotherapy,
one
the report.
Before
such
Ten
four T,-N,,
two
received
post-
period,
and the remaining
to 69 months
after operation
undertaking
Such
a
has been
Syracuse.8’
postoperative
alive seven
is mandatory.
carsome
shared.’3
It
demon-
patients.
approach
form
tu-
atypical
involves
would
not be widely
yet to be systematically
died
in the
nine
were
at the time of
surgery,
extensive
CAT scanning
has been
reported
to result
in upstaging
clinical
stage
1 and 2
SCLC
cases to stage 3 in 75 percent
of cases.65
As previously
mentioned,
tumor
recurrence
in the
chest at the primary
disease
site is a frequent
problem
only
also,
with
in patients
although
Chest
treated
to a lesser
chemotherapy
plus
with chemotherapy
extent,
in patients
thoracic
The
group
at Syracuse
has
failure
in the primary
disease
alone
treated
radiation
therapy.’
attempted
to
site by treating
2
apy and subsequent
distant
metastases,
surgical
resection.8’
Patients
with
contralateral
mediastinal
nodes,
involvement,
disease
by
(N,, M,) with
decrease
patients
with
clinical
stage
mediastinal
metastases
superior
malignant
pleural
effusion,
were excluded.
Operations
weeks
vena
treatment,
of tissue
of having
chemother-
virtue
initial
cava
obstruction,
and poor general
were undertaken
of chemotherapy
the volume
known
condition
after six
aiming
to have
been
to resect
involved
with
tumor
before
chemotherapy.
Of six patients
treated
in
this
way,
one
developed
hepatic
disease
after
26
months
and the remainder
were in remission
at 25, 16,
13, six, and five months
after operation.
Only
a few
SCLC
patients
will be’found
to be eligible
even fur the
most aggressive
ies at Vanderbilt,
of surgical
we have
Since
only one-third
stage
at presentation,
little less than
According
in those
sis
is
trials.
In preliminary
studfound that only 28 percent
of
SCLC patients
are suitable
approach
reported
by
10 percent
to these
few SCLC
for the aggresthe
Syracuse
of SCLC
this would
of all SCLC
for unresectability
have
eral medical
condition,
T, N, M,
Stage
operative
SCLC
are actually
necessarily
1 and stage 2 patients
were
resected
for
group.’5
limited
(4.7%)
“nonsecretory”
administered
chemotherapy-surgery
limited
stage
sive
surgical
3,133
post
all
in
which
which
which
although
in
stage
T,-N,)
carinal
400
patients
with SCLC
who were seen at the Bromptom
Hospital
over 15 years,
40 were resected
for cure.
Ten
(25
percent)
survived
five years.
Neither
chemotherapy nor
radiotherapy
series,
although
the
be
not
but
Veterans
Group’s
entire
experience
In this large
experience,
had
H
five-year
the
that
should
combined
staging
were
a 36 percent
et al76 reviewed
for cancer
reported
(stage
Among
demonstrated
In 1982,
resections
disease
in this small group of patients,
that surgery
may be beneficial.
nodules.
Administration
Lung
resection
of SCLC.
3,133
have
after resecof all SCLC
and his associates7’
reported
Administration
experience
pulmonary
survival.
resectable
However,
evidence
to
strated,
reported
to
seems
obscured
the occasional
long-term
survivor
tion. Only a minority
(less than 10 percent)
patients
surgical
a contraindication
of diagnosis
subtype,7’
of
included
and poor
patients
constitute
patients.
Most
tumor
location,
genpulmonary
function.
investigators
adjunctive
chemotherapy
following
The combined
use of surgery
and
exciting
new
experimental
patients
with
limited
therapy
must
still
be considered
would
for
However,
advise
a subset
of
this
of
type
investigational.
Small Cell Lung Cancer
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21409/ on 05/05/2017
operation
at diagno-
surgical
resection.
chemotherapy
is an
approach
disease.
a
Reasons
findings,
we believe
that
cases which
are low-stage
reasonable.
are
(Hande,
Des Prez)
cell
54
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cancer.
Maurer
et
LH,
al.
A
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Tulloh
randomized
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of the
apy-radiation
apy
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