Sensitivity - Clinical Cancer Research

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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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