chemotherapy. Selection ofindividualized chemotherapy regimens is labor intensive but feasible ... is more sensitive. Patients with limited-stage. SCLC are twice as likely to achieve a complete ... Downloaded from ...... J. C., Grayson,. J., Minna ...
Vol.
3, 741-747,
May
Survival Treated in Vitro
Clinical
of Patients with with Individualized
Drug
Patricia
Cortazar,
Edward
Russell,
Daniel
1997
C. thde,
Sensitivity
Adi F. Gazdar, Seth M. Steinberg, and
Bruce
Limited-Stage Small Cell Lung Chemotherapy Selected by Testing
Edward
Woods,
John
Williams,
chemotherapy. is
SCLC.
E. Johnson’
National Cancer Institute-Navy Medical Oncology Branch [P. C., A. F. G., E. R., D. C. I., B. E. J.], Biostatistics and Data Management Section [S. M. S.], National Cancer Institute, and Department of Surgery and Pathology [E. W., J. W.], National Naval Medical Center, Bethesda, Maryland 20889-5 105
Selection
regimens
labor
Treatment
with
was associated ever, because ofthe
Our purpose Individualized
sitivity cell
lung
was to study chemotherapy
testing cancer
and survival.
the feasibifity of determining regimens by in vitro drug sen-
(DST) for patients with limited-stage (SCLC) and to evaluate patient
Fifty-four
small response
previously
untreated patients with limited-stage small cell cancer were studied. Fresh tumor specimens for DST were collected, when possible, from patlents’ biopsies before the start oftreatment. The differential staining cytotoxicity assay was used to determine the in vitro sensitivity of the tumor cells to different drags. From these resUlts, an in vitro best regimen (IVBR), a three-drug combinatlon of previously proven efficacy of seven active drugs in SCLC, was selected. Patients were initially treated with four cydes of etoposide/cisplatin and concurrent radlotherapy. This was followed by four cycles ofeither individualized chemotherapy regimens based on the results of DST or, when DST results were not available, four cydes of vincnistine, doxorubicin, and cyclophosphamide. Eighteen patients (33%) underwent biopsy procedures that provided tissue specimens for DST. The biopsy speCimens contained tumor cells In 16 of 18 patIents. The median duration from diagnosis to start oftreatment was 22 days (range, 4-58 days) for the 18 patients who underwent elective thoracic biopsies compared to 21 days (range, 2-74 days) for members of the group that did not (P2 0.58). TIme from thoracic biopsy to initiation of chemotherapy was a median of 4 days (range, 2-22 days). DST was done in 10 patients, and IVBR was administered to S patients. The median actuarial survival of 8 patIents treated with their IVBR was 385 months compared to 19 months for the 46 patients treated with empiric
chemotherapy in limited-stage
feasible
individualized
IVBR
in our
pa-
nature
patient survival; howstudy design, other factors
ofoun
have affected the results.
could
INTRODUCTION have
developed
numerous
types
of in vitro
DST2 for identifying drugs more likely to kill the tumor cells a given patient, attempting to increase the therapeutic efficacy
of of
chemotherapy. Clonogenic, coborimetric, rapid [3H]thymidine incorporation, and chemotherapy treatment of athymic nude mice with implanted tumors have all been used to assess the sensitivity
of tumors
otherapy few
and
regimens
have
prospective Investigators
patients
with
otherapy
tumor
cell
regimens
initially
for individual cytotoxicity to distinguish
effects
cells
on normal
vitro chemotherapeutic lation of tumor and
(13,
effect normal
SCLC
tic agents
by DST
a partial
response
relapsed
after
(1-6).
showed
was
studied
14).
This
allows
(10).
patients
Therefore,
that
selection
Patients
from chem-
(11,
12). The
of in popuwith
of chemotherapeu-
who
were
with
administration
assessment
had no response
of treatment
response
treated
a
tumors
cells in a mixed study of patients
and
treated
DST had been done. Four of 16 (25%) regimen selected by DST had a complete 3 of 43 (7%)
in only
to select
in 1983
on cancer cells. The
12 weeks
a complete
SCLC
patients
chem-
results
assay was used in these studies cytolysis of tumor cells from
feasible.
after
Patient
by assay
and extensive-stage
differential staining because it is able
extensive-stage
lines
been selected
studies (7-10). in our branch NSCLC
or
those
with
who
IVBR
if
patients treated with a response compared to
an empiric
regimen
of chemotherapy
of VAC
selected
vitro was feasible in a subset of patients, and selected by DST seemed to be at least as active
by in
the regimens as an empiric
regimen. There select cancer twice
may
(15).
compared
Therefore,
chemotherapy
2
be a greater
potential
utility
of using
DST
to
chemotherapy agents in a clinical situation in which the is more sensitive. Patients with limited-stage SCLC are as likely to achieve a complete response after chemother-
apy treatment
Received 12/2/96; revised 1122/97; accepted 1/29/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I To whom requests for reprints should be addressed, at Head, Lung Cancer Biology Section, National Cancer Institute-Navy Medical Oncology Branch, Building 8, Room 5101, National Naval Medical Center, Bethesda, MD 20889-5 105.
an
741
Cancer
individualized
but
Research
with prolonged
tients
Investigators
ABSTRACT
of
intensive
Cancer
The abbreviations
we regimens
used
to patients decided for
with
to
use
patients
are: DST,
drug
extensive-stage in
with
vitro
DST
limited-stage
sensitivity
testing;
disease to
select SCLC
NSCLC,
non-small cell lung cancer; SCLC, small cell lung cancer; IVBR, in vitro best regimen; CCDP, cisplatin; CCNU, lomustine; CTX, cyclophosphamide; DOX. doxorubicin; NM, nitrogen mustard; VCR, vincristine; VP-16, etoposide; VAC, vincristine, doxorubicin, and cyclophosphamide; MTX, methotrexate.
742
Survival
of SCLC
because
Patients
the in vitro
stage
setting.
have
tumor
DST
Patients tissue that
against
SCLC
lieved
from the
it was
noscopies, DST.
their
13-24.
Surgical
biopsies
to undergo tumor
performed
lymph to obtain
requiring
procedures.
collected
on
NSCLC,
Although
for in vitro
the
safety
we believe
patients
with
tively
and
collected
could DST
because more
rapidly
information
obtain
the
from
diagnosis
biopsies,
and treatment
was
visit
four courses by in vitro
available.
We
of patients with
evaluated
an empiric
an P/BR
VAC
were
to treatment compared
with
AND
Previously
individual centrations
with
who
with by
pany)
senot
ratio
for cell
survival treated
The
specimens were reviewed (J. W. or A. F. G.). Patients
small
cell
carcinoma
also
The
protocol
board,
and
patients. therapy,
eligible was
written
Before patients
were
for this study.
SCLC
considered
mixed
with
for this
by one of the with predomhistological
type
study.
approved
by the local
informed
the initiation underwent
another
consent
institutional
was
review
obtained
of chemotherapy staging evaluation
and
from
and
identified
criteria
for patient
entry
were
chest radioas described
as described
previously
who
superior
vena
therapy were with enlarged biopsied cells, they
cava
of SCLC of lobar syndrome,
identified before supraclavicular
before
starting
treatment.
for in Vitro
or mainstem or other
acceptable
candidates
DST.
airway
need
Patients obstruction,
for urgent
chemo-
the start of treatment. Patients lymph nodes had such nodes If the nodes
patients were not considered for elective had no enlarged supraclavicular lymph
considered
made
for
contained thoracotomy. nodes and
an elective
SCLC if were
intrathoracic
included
a reference
10-fold
lower
con-
(10).
The
previously the SCLC
VCR,
cells included and NM (used in
MTX,
activation when the
in vitro). These extensive-stage
has been
design
during
and
used
incubation.
stained
with
nigrosin
dyes
(Sigma
counterstained
with
H&E.
Living
ability
surviving and
to exclude
tumor
cells:
drug-exposed
(J. T. Baker
Chemical tumor
cells
samples.
duck red control to
Cytocentrifuge
Fastgreen duck
Comcells
were
and nigrosin.
The
was
compared
in
survival
of
mean
If the
seven SCLC
in this study
Fastgreen
and/or
by their
cell
of seven
cell
survivals
at the reference
concentration(s),
was less than 50%. patient was selected
regardless
from
the DST
data.
Of the 35 possible 3-drug combinations individual drugs tested, 13 were reported
resulting from the 7 to be effective against
lung
from
cancer
(10).
combinations mean testing
We
chose
the
by determining
system
were
the scope
MOdality
these
with
consisted of four chest radiotherapy
P/BR
cycles
of
of this
the
VAC
13
lowest In vitro in the in
study.
Regimen.
dality regimen with concurrent or four
among
reference concentrations. or drug-drug interactions
beyond
The Combined
IVBR
the combination
cell survival at the of drug combinations
vitro
The
combined
mo-
cycles of VP-l6 and CCDP followed by four cycles of an when
DST
results
were
not
available (17). The initial 12 weeks of therapy consisted of VP-l6 (80 mg/m2) administered on days 1, 2, and 3, and CCDP (80
(17). Elective Biopsies had no evidence
Tumor
cells was less than 50% at the reference concentration, a drug was considered to be active against the cell line. The best drug or drugs for each cell line were those that had the lowest
all
previously (17). Information regarding dates of diagnosis, first clinic visit, biopsy, and initiation of treatment was recorded. Eligibility
(18).
and
be
tumor
and
cyto-
or cytology pathologists
could
concentrations
against
requires in 1983
proliferation
Co.)
controls
tested
DST
and were
by Weisenthal
DSTs
as described
the same
were
of
the
higher
CCNU,
DOX,
before
three
tumor
were handled cell numbers
4 days of incubation, acetaldehyde-fixed added to the cell suspensions as an internal
were
Chemical
or
documented
were
agents
preparations
initially
of
were
anesthesia to oheligible for treat-
described
concentrations
drug,
designed;
After cells
all
as 10-fold
each
CCDP,
correct
elapsed
those
histologically
logically
(16)
of
media assay
oncology, they
for intrathoracic
obtained (10). Tumor
with
These
was
prospec-
for
as well
study (15).
in
METhODS
pathology reference inant
drugs.
not opt
in selective
of whether cell survival The P/BR for each
patients
staffs,
did
incubated
from
regimen.
untreated
radiation
exclusion
used
were
concentration
tumor
PATIENTS
was
of C’FX, which were selected
was performed
Patients
(13)
suspensions
place drugs
combination regimen, if DST results were
the response
with
time
oncology, anesthesiology
Specimens previously
dye
VP-16,
standard-dose VP-16/CCDP This treatment was followed
of a three-drug DST, or VAC,
treated
a biopsy
was evaluated.
treated with four cycles of concurrent chest radiotherapy. either lected
and
until
The
with
of patients
complications,
clinic
initiated
We
(15).
by culture
chemotherapeutic
disseminated
the number
multiplied
been
number of specimens from which performed. The time required to
surgical
and first
has
information
widely
growing
about
be biopsied and the could be successfully
used, so on the safety
in patients
to collect
it is more
for
been
procedures
it is important
SCLC
the mediastinum
of these
solely
information
and
if they
Vitro DST. as described
et a!.
tissue
anesthesia
extensive
proce-
study
In cultured performed.
mediasti-
obtaining tumor tissue for DST have infrequently we believed it was important to obtain information of these
treatment
biopsies,
tumor
general
for in
surgical
node
ment on this biopsy.
be-
a biopsy
for chemotherapy
medical
an intrathoracic biopsy under general tumor tissue for DST. Patients were still
tam
tissue
the
offered
active we
by
surgery,
SCLC more
Therefore,
patients
We
thoracotomies
were
biopsy
cardiothoracic
anesthesia.
extensive-stage
to obtain
supraclavicular
and
local
regimens
regimens
in weeks
including
with
tumor
do not typically
under
regimens.
to ask
to select
administered
empiric anesthesia
vitro dures
the
general
under
DST
our patients selected
in the extensive-
SCLC
for biopsies
appropriate
procedure
feasible
limited-stage
in vitro
than
with IVBR
had proven
with
available
The data collected suggested
Treated
mg/rn2)
on day
1.5 Gy twice VP-16/CCDP pletion
1. Chest
daily fractions chemotherapy
of chest
radiotherapy
radiotherapy,
therapy was given for 12 weeks the number of tumor cells from
DST (10). Selection treatment depended a cell procured
line
established
from
and
at weeks
to allow patients’
of chemotherapy upon
the patient.
was
administered
at
for 3 weeks to a total of 45 Gy. The was repeated at week 4, after com-
whether from
specimens
for the final DST
could
a pretreatment
If DST
7 and
results
10.
Initial
time for an increase
were
required
12 weeks
be performed tumor available,
in for
of on
specimen 1 of 13
Clinical
PATIENTS
Cancer
Research
743
ENTERED
54 (100%)
IBIOPSY L
NOT
PERFORMED
BIOPSY
PERFORMED
36(67%)
18(33%)
I Diagram of the number of patients entered in the protocol and their selection process. Numbers in parentheses, percentages of all patients entered in this study.
[
Fig.
NO TUMOR
IN SPECIMEN
TUMOR
IN SPECIMEN
2 (3%)
16 (30%)
DST NOT PERFORMED number of cells)
DST
PERFORMED 10 (19%)
IVBR
TREATMENT 8 (15%)
(Inadequate
6 (11%)
standard the
3-drug
3 most
combinations
effective
that
drugs
most
in vitro
closely was
weeks (10). If results were not available, on day 1 with VCR, 1.4 mg/m2 (maximum 45 mg/m2; and CTX, cycles, chemotherapy during
these Response
weeks
1000 was
of combined-modality
physical copy
therapy
examination,
chest
washings
and biopsies,
with
liver, and treatment, repeated attained. scribed
radionuclide only those
Kaplan-Meier to compare
bilateral
bone
method
bronchosaspirate
(Fig.
The
was
small
patient had involvement median bulatory
Mantel-Haenszel two
groups
model
was
also
(21).
(37 men
cell cancer patients
limited-stage of inguinal
of last using test
was
of patients used
with
a performance patients
a performance group.
status
with
and
used
(20).
Fifty status
1986
limited-stage small
and July SCLC,
cell lymph
in the DST
status in the
treatment
group.
of 2 and one patient empiric
chemotherapy
with
airway
syndrome,
by
status:
2 patients
1 patient
One
and
had
The
6 patients had
patient
tumor
There was specimens
chronic was
had
a
a neurologic
inadequate
pulmonary
underwent
under
contained
reserve
tumors
effusion. to pro-
a left upper
procedures failed to reveal a diagnosis. of a supraclavicular lymph node, and
had mediastinoscopies
had
the
obstruc-
mediastinoscopy.
medical
disease,
for DST.
specimens
There
started duration
for
with The
poor
artery
tissue
15 patients
ment
1993
cancer nodes.
cava
had
syndrome,
tumor
breath initial
and
vena accessible
refused
general
cells
no evidence from two
anesthesia.
in
16 of
The
18 (89%)
of tumor in mediastipatients. One of these
obstructive
pulmonary
judged
to be inadequate
disease,
and
his
to undergo
an
or lobectomy. The other patient lymph node that showed no cancer
cells.
the
treated
or mainstem
not
patients
8 patients
tests, and 1 patient had a small right pleural patients (33%) underwent a biopsy procedure
biopsy
A
of 54 patients were fully amof 0 or 1. One of the patients
of 2 was
of 3 were
July
were
lobar
elective parenchymal biopsy had a biopsy of a mediastinal
are two-sided.
17 women)
between had
a performance
status
paraneoplastic
pulmonary folthe
to evaluate
All P values
extrapulmonary and retroperitoneal
age was 58 years. with performance
Two
of coronary
Thirty-six
Of these,
superior
10 patients
biopsied patients. nal lymph node
calculated
until the date were generated
between
on survival
1 ). Fifty-three
were
had
lobectomy because other Two patients had biopsies
RESULTS limited-stage
had
4 patients
vide
response had been were defined as de-
duration
initiation curves
(19).
patients
3 patients
from
patients
hazards
Fifty-four
tion,
function Eighteen
scans of the chest and tomography scans of the
Survival
the survivals
of variables
12
Biopsies.
procedures.
1 1 patients
remaining
and
Elective
had no biopsy
history
on history marrow
(67%) procedure,
bone scan. At the end of 24 weeks of tests that were abnormal at 12 weeks were
(17). Analysis.
proportional
(1 1). after
fiberoptic
to determine if a new complete Complete and partial responses
previously Statistical
effect
based
radiograph,
from the date of treatment low-up or death. Survival
Cox
described assessment
was
and biopsy, computerized tomography head, radionuclide or computerized
12
3 weeks. After four Dose modifications
have been Response
Pretreatment
to for
patients were treated dose, 2.0 mg); DOX,
mg/m2, every discontinued.
treatment periods Assessment.
corresponded
administered
4-58 1
biopsies
were
was
no surgical
interrupted
from fluid overload while cisplatin administration. the following from diagnosis days)
for the
compared
was 0-62
from thoracic (range, 2-22 7 days required
One
patient’s
he developed
18 patients
of
before safely
the re-
receiving hydration The treatment was
who
to 21 days =
underwent
(range,
The to treatment 0.58).
2-74
elective days)
treat-
shortness
day with no complications. The to start of treatment was 22 days
patients who did not (P2 clinic visit at our institution patients (range,
complications.
for 24 h, after
median (range, thoracic
for
the
36
median time from first in the group of biopsied
14 days (range, 7-28 days) compared to 10 days days) for the group not biopsied (P2 = 0.07). Time biopsies to treatment was a median days). Five of 18 patients were treated
after the biopsy. One patient had 2 weeks to recover from the surgery,
of 4 days more than
a lobectomy two patients
and had
744
Survival
of SCLC
Table
Mean
1
Statistics with IVBR.
Patients
Treated
with IVBR
in vitro cell survivals
on each of the seven
Variable
f
n
SE
VP-16 CDDP DOX NM VCR CCNU MTX
56 71 63
8 8 8
13 9 9
57
8
72 62 78
8
produced
drugs
Minimum
Median
4 33 12
45 73 68
11
22
48
7
48
71
8
12
4
66
8
7
56
75
their tient
staging evaluation completed developed a small pleural
thoracenthesis,
and another
after effusion
patient
Table
treated
provided
the results
within
in vitro
in vitro
12 weeks
selection
12 weeks from
successful
Drug
of treatment.
whom
tumors
of all patients.
The
other
number
of tumor
cells
ogeneity
in the
sensitivities
the mean 1). VP-l6
percentage
mined (Table
cells
6 of
from
but only
to allow of the
were
procured had
considerable
a median of 45 and 48%, respectively, had DST. The median for the combined
a surrogate
for C’FX,
for individual cell survivals,
drugs with
therapy.
Of the
who used
most
active
antitumor
the
therapy
of lung
3-drug
of 54 patients
5 were
MTX
were
(98%)
second patient VP-l6/CCDP
treatment
4 cycles
3 months
infarction the planned
during course
of 52 (85%)
for their
patients
as an WBR,
second
who
underwent
were
based
were
a biopsy,
patients
had
ditional
chemotherapy
their fifth progressed
unacceptable
the
through during
toxicity. after
Fifty-
patient
four
cycles
with
of
empiric
second completed Fourteen
eighth cycles (two
12
(Table
(25%) By week
patients
(87%)
tinued
that
to be activated
in
weeks
of
cycles of therapy; 5 and 6, and nine
patients patients)
declined and
toxicity
44 patients
adseven
IVBR,
references
for
of
cited
in
to Chemotherapy.
response.
during
who
their
The initial
eventually
other
two
12 weeks
of
VAC,
32
received
had
had
a complete
became
complete
(27%) had who later
and
responders,
11 of
with
P/BR,
and
1 patient
44
7 of 8 con-
responder. beginning
response
a partial
response,
had a partial response. 24, after 12 weeks of therapy
Of the 54 patients
treatment,
at 24 weeks,
whereas
40 patients
(74%)
12 patients
(22%)
response.
The median is 6.1 years.
between
potential Results
DST
follow-up are updated
Data
and Patient
of patients to March
Survival.
enrolled in this study 1996. Eight patients
are still alive and free of SCLC; 46 patients have died. The median actuarial survival was 21.4 months, with 83% survival probability
at 1 year;
actuarial
20% at 5 years. The empiric chemotherapy in patients
their
in patients
treated
the difference the who
P/BR
biopsied
survival
median (VAC)
comparison of the entire survival of patients who received
4 cycles of patients began
received
and schedules
Doses in the
Response
drug
as a partial
months
2).
and
evaluable
Relationship
For 8 of 18 (44%)
Three
five cycles
One
treated
of DST
Thirty-eight of 54 patients (70%) second 3 months of chemotherapy.
but did not complete two patients’ cancers
after
of therapy.
on the results
patients
of IVBR.
were
(75%)
patients
of VP-l6/CCDP
of therapy.
patients
3 months
needs
received IVBR were partial responders at week 12. After 12 weeks of empiric chemotherapy (VAC), 21 (66%) of 32 partial responders had a complete response. Hence by week 24, 33 of
each
the 3rd week of therapy, of chest radiotherapy. A
died of a perforated intestine and chest radiotherapy.
Forty-four VAC
in
course of 4500 cGy of chest 3 months of therapy. Two
the first
which
patients (73%) had a partial response, and 12 patients a complete response at week 12. All eight patients
not
previously
Administered.
received
during
died
selected
Therapy
patients
died of a myocardial before completing
used
from
had a complete
and a full planned during their initial
37 12 12 12 25
are described
patients
44 patients
2).
chemotherapy radiotherapy
their
and
combinations
cancer,
selected 1-3 times (Table Combined MOdality
three
VCR,
cycles
of DST
died
at all.
Of the 13 possible
3 1 1 1 2
3.
patients
tested.
CDDP,
Table
four
treatments
deter-
most
drugs
received
IVBR
We
lines.
Of the eight
Correlation
from five of eight patients (Table 2). DOX, were selected one time each as the single
active
patient).
Fifty-two
cell
the
(one
heter-
for the eight patients three P/BR drugs
was
cycles
an inadequate
agent in specimens VP-16, and CCNU selected
12 12 62 12
one received VAC in the first cycle (while waiting for DST results) and P/BR in the remaining three cycles. The other seven the
46%.
NM,
1 1 5 1
vitro.
patients
or 15%
There
of cell survivals showed the lowest
second
18 patients
18 patients was
had for an
for the
44%
tumor
10 pa-
8 patients
treatment
biopsies
of the
and NM
SCLC
represents
for DST.
Percentage
hyponatre-
chemotherapy
containing
NM was used in place of CTX,
a
in
replacement.
of starting
This
Frequency
Individual VP-16 DOX NM CCNU P/BR combination CFXIVP-16/CDDP VP-l6/CFX/DOX DOX/VCR/CTX DOX/VP-16/CDDP CFX/CCNUNCR
100 100 100 100 100 100 100
symptomatic
DST,
of combination
Frequency of selection of drugs as the most cytotoxic drugs or inclusion in the IVBR three-drug combination eight patients”
2
individual
Maximum
their biopsies, one parequiring diagnostic
had
of malignancy requiring electrolyte DST and Selection of IVBR
tients
was
drugs
patients
mean.
a
mia
by individual
for the eight
was
with
38.5
received
IVBR. to separately
their
months
at 2 years
and
P/BR
(P2
=
compared
with
IVBR
for
0.035)
the median biopsy and
to 17.5 months (P2 = 0.0074)
for
the curves.
The mean of the three lowest agents used in treatment was
constructed
44%
curve (Fig. 2). In addition, underwent elective thoracic
but not treated
between
was
survival of patients treated with was 19 months, compared to 38.5
A Cox
cell survivals and the mean of formed for the eight patients
hazards
proportional
evaluate
the
effect
of these
model
was
variables
Clinical
Table
3
Doses
and schedules
of the IVBR
patients received four cycles of chemotherapy. 6 weeks. All drugs were given i.v. except CCNU, which hematological toxicity. No. of patients
CFX/VP-16/CDDP (27) VP- 16/CTXIDOX (28) DOX/VCRJCTX (29) DOX/VP-16/CDDP (30) cTX/CCNUIVCR (31) aDay 1. bDays 1-3. C Maximum dose, 2.0 mg. dDay 22.
VP-16 (mg/m2)
C7X
(mg/rn2)
3 1 1 1 2
combination
used in eight
Research
745
patients.
All regimens were given every 3 weeks except CTX/CCNU/VCR, which was given every was given p.o. Doses were modified from previously published regimens to produce similar
All
Drug combination
three-drug
Cancer
750” 750” 1000”
CDDP (mg/rn2)
80” 80”
40”
80”
40”
DOX (mg/rn2)
VCR (mg/rn2)
45” 45” 45”
CCNU (mg/rn2)
1 #{149}4UC
1a.d
70’
14a.e.d
.-.
IVBR 5/8 Died
0-0
NO IVBR 41/46 Died
100 90 80 -I .(
70
> >
Fig. 2 Actuarial survival of patients who were treated with their IVBR (#{149}) compared to that of patients treated with empiric chemotherapy (NO IVBR, 0). Tick marks, patients still alive.
60
P2=0.035
U)
z
w C) w
a-
2
4
6
SURVIVAL
on survival.
Having
higher
three mean
lowest cell survivals of the three IVBRs
risk,
1.03)
conveys
values (P2 used
it is likely
a slightly
these
greater
of 47%.
more vival
cells
risk
effects
of death,
on survival,
The cell survival
data
but
not
the patients’
that the
agents that of 44%. The had a median
survival,
we selected
to divide the patients into those whose sensitive and those whose tumor cells are
are more
resistant (which of the two values
DISCUSSION
roughly corresponds 44% and 47%). The
to the median
Patients
median sursurvival of
ment. no
significant
those
who
treated
Kaplan-Meier have a better
analysis survival
not approach
standard
suggested with lower statistical
45%
cell
survival.
Therefore,
there was a slight tendency values, but the difference significance
(P2
=
0.45).
to did
the
with
empiric
come.
so other
One
airway
chemotherapy
showed
that
compared
bias
group.
similar
In addition,
stage cells
to that
vena
cava
cava
syndrome
(23, 24). SCLC
showed
to be established
assignment
of patients
was
outcome
the
treatment
cava
of our
studies
study
and
without
obstructive
of patients between
as a cell
line and survival
with
the
effect
SCLC
presence on treatment
with
the ability (10).
study
obstructive
of patients
no correlation
with
to the ema recent
that
not out-
of patients
SCLC
showed
treated was this
syndrome
had no adverse
Our previous
8 patients
study
However, with
syndrome
for
influenced
of patients
two
a
to 21 days
The
have
had
treatment
of 44 patients
0.035).
vena
(22).
survival that
treat-
biopsies
began
could
was
atelectasis
vena
than (P2
atelectasis superior
The
longer
or superior
the survival
underwent
diagnosis, a biopsy.
biopsied
assay-selected
of chemotherapy
who
and
factors
potential
obstruction
piric
12 weeks
chemotherapy
randomized,
be safely
different
complications after
was
could
with
18 patients
did not have IVBR
SCLC treated
second the
surgical
with
superior
than
and
of 22 days
vitro
more
during In our study,
and
showed
limited-stage
of patients
regimens
patients whose in vitro DST showed less than 45% cell survival was 38.5 months compared to 21 .4 months for patients whose in DST
with
in a subset
median
Kaplan-Meier indicated
(the chemotherapeutic had a median survival selected for the IVBR
To compare
45% as the percentage tumor
of the
reasonable to state that there these parameters and survival,
limited
was performed.
three most active drugs caused the most cell kill) three chemotherapy drugs survival
the mean
to be limited.
To examine analysis
either
relative risk, 1.02) or the in treatment (P2 = 0.10; relative 0.13;
significantly so. It is probably could be an association between but
from
8
TIME IN YEARS
extensiveof tumor Therefore,
of
746
Survival
of SCLC
the fact otherapy syndrome
that some of the patients treated in the empiric chemgroup had obstructive atelectasis or superior vena cava should not have altered the outcome of the study. The
extensive
Patients
selection
patients
who
process
would
Three
longer
other
specimen
groups
This
randomly
a single
actually
4 of 19 patients
(21%)
there
therapy
with
compared
by Wilbur
lung
NSCLC
were
able
differential
staining
laboratory,
and
patients Yamaue
a partial
of 78 patients
were
31 patients
patients sponse,
with
able
were
with
of their
NSCLC,
DST
with
36 of
tumor
with
by the
reached
the
an P/BR.
who
had
were
(9%)
patients
pared
to 10 of 69 (14%)
DST) treated
(22%)
tumor,
treated
with
performed
an IVBR.
P/BR
and with
had
patients
36 patients
(9). and
patients an IVBR.
a clinical with
empiric
published
studies
and
these
investigators
were
22-75% of the tumor samples 12). However, only a minority
In our
study
to have
able
that reached of patients
a relationship
patient
response
a tumor
specimen
patients’
response
with
and
(4, 6, 9). Based
on this
obtained fore, only participation regimen
from
a tumor
specimen
et al. (9), only
180 patients
seen
reach
45 tumor
to chemotherapeutic
in consultation
(25%).
The
success
selected
by in vitro considerable
have sensitivity study
between and
that
the
study
of 45
in vitro
prolonged
cancer
survival
cells
have
hetero-
agents and the close sensitivity of different
(25),
on DST
of this
perto
analysis of 30 patients a prospective study of 7
agents
patients
to
survival because
of 21 corn-
proin
(9,
were There-
we believe
for the
makes
randomized
it is im-
screening
it difficult
at the
at the only
IVBR
continued,
of new gemcitto evaluate
of treat-
beginning
a study
to demonstrate P
=
a 20%
level
0.05
with
15% of the patients
vitro
SCLC. The demonstrate based stage
this
selected
80%
for
major achievements that the selection
amplification
and
power.
However,
our study
were
prospective
patients
91
in 2-year able
to
patients such a
study
of in
with
limited-stage
from this study of individualized
have been chemotherapy
on an P/BR is feasible and SCLC and that the regimens In addition, this SCLC patients
require
need to enter 1229 We do not believe
is the first published
chemotherapy
would difference
entering
be treated with an IVBR, we would to find a 20% difference in survival. trial is justified at the current time.
to
safe in patients with limitedselected by DST were cm-
study provided for biological its association
tumor cell lines of studies, including with
survival
(26).
This study provides information about the safety and feasibility of elective biopsies under general anesthesia for obtaining tumor tissue apeutic agents. against
in the sensitivities
inadequate
DST in a randomized trial. Only 15% of the patients entering our limited-stage SCLC trial could be treated with an IVBR. A
of
DST. heterogeneity
rate
we and
chemotherapy agents that are now available as taxanes, abine, vinorelbine, and topoisomerase inhibitors.
able
13-25% of patients with lung cancer evaluated for in these trials were able to be treated with a
We observed
SCLC,
we had
a correlation
working
of drug system
sensitivity
A prospective
to chemotherapeutic in vitro and in vivo
to continue
(58%
the laboratory. specimens
tumor
study,
survival.
showing
12). The
combinations
extensive-stage
remission
data
portant
oncogene
had
(10,
showed that 20 with NSCLC
different
vitro
for were
In vitro testing in the in vitro
present
showed
cancers
(75%),
by Wilbur
and
complete
geneous sensitivity relationship between
ically active. limited-stage
respectively,
SCLC
sensitivity
an
for DST
in
In the
rates
arm
the laboratory (7-10, entering a prospective obtained
with
between (10).
per
DST
SCLC
selected
Our
selected
regimens
to evaluate this issue. Other investigators DST and compared the in vitro tumor
with
chemo-
to perform
8 different
with NSCLC for 25 patients
DST
of patients
found
10, 12). In this study and in our study of patients with extensivestage SCLC, only 16 of 54 patients (30%) and 60 of 80 patients In the study
the in vitro
other
different
patients.
were
extensive-stage
study of patients were selected
patients
other
with
that
five
of eight
regimens
of chemotherapy for different patients. combinations or drug-drug interactions were beyond the scope of this study.
However,
(12). In our previously
and
to what
selected
for the treatment
for 26 patients
treated
response
treated
similar
DST
that 6 different
NSCLC,
reof
Two
tested,
ment to either empiric chemotherapy or an P/BR selected by DST would require a large number of patients entering the trial. If the trend in prolonged survival observed in our patients
tumor,
were
21 patients
with
trial comparing
of 31 (32%)
had a clinical (7). In our study
1). The
showed
other prospective different regimens
The
on their Ten
therapy responses
161
on their
able
advanced
performed
if their
treated
for
A study
had a response rate of 36% with solid tumors (n = 54)
to have treated
those
trial were
tumor
assay were
performed
studies,
the 2 groups. chemotherapy
24) with the (3-(4,5-di-methylthiazol-2bromide (MTT’) assay. Sixty-eight
DST
spective
to DST-
35 of 45 patients
their IVBR 78 patients
have
therapy
between selected
drugs
combinations
patients
Al-
empirically,
tumors.
treated with assay-directed 5 complete and 5 partial
patients
response treated
to the (Table
patients with NSCLC, a retrospective with non-Hodgkin’s lymphorna, and
DST-
agents.
of solid
DST
patients
treated with et a!. studied
those
found
studies
numbers formed
by a
to receive
with
a variety
cytotoxicity
malignant ascites (n yl)-2,5-diphenyltetrazolium and
had
showed
to have
25
random-
selected
randomized treated
and
three-drug
their
encountered
prospectively
to 1 of 36 (3%)
cancer
et a!. (9)
have
chemotherapy
was no difference in survival Two other uncontrolled studies
patients
institution
to select
lines
have
(9). Therefore,
the
1).
our
DST and
in
advanced cancer, some of whom (8). In this study, 65 patients
(28%)
were
selected
and culture
68 patients were randomized to receive by an in vitro capillary cloning system.
patients
therapy
with
to receive
the other selected
19 of 68
though
procedure
tumors
includes
assigned
clinician, and chemotherapy
type
cell
authors other
regimens However, in
outside
patients
in solid
of tumor
selected
of investigators
regimens
problems.
selected
selected
the different
chemotherapy but workable.
collection
ized study of 133 patients with had had previous chemotherapy
Only
despite
have
or IVBR).
studied
chemotherapy
were
1 could
only 15% of the patients participating able to be treated with an IVBR (Fig.
prospectively
similar
in Fig.
of individualized is labor intensive
of the consistent
methodology, protocol were have
lived
(empiric
The selection based on DST data
with IVBR
shown
have
of chemotherapy
spite
Treated
and
lung improving
for laboratory The continuing
cancer
with
technologies
investigations introduction
different
in vitro
for evaluating
for selecting of agents sensitivity in vitro
theractive patterns
drug
sensi-
Clinical
tivity
may
make
testing
possible
future
trials
number
a randomized in the future.
to be
of patients
able
trial
to obtain
entering
evaluating
We suggest tumor
in vitro
drug
that investigators tissues
plan
from
a large
16.
ACKNOWLEDGMENTS We thank Dr. Larry Weisenthal for his critical manuscript and for his helpful suggestions.
review
of this
Research
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