Ifosfamide, cisplatin, vinblastine combination chemotherapy in the treatment of advanced non-small-cell lung cancer

272

tin + lomustine.The hypotheticalsuperiorityof this regimen was based on data from experimental animal tumors suggestingpotentialedefficacy of the three specific combinations. A mtal of 234 patients were included.and 113 vs 108 patientswereeligible. Median survival in bolh gmups was 48 weeks @ = 0.89). Complete remissionswere observedin 36/101 and in 42/99 patienu evaluable for response. There was no signilicantdifferenceinresponseduration.A~restagingafter 18months ofcherolhaapy27patienu(l6%)and22padents(16%),respectively, were free of disease. Six patients, three in each arm, are.still alive, 8+ to 10.5+ years after diagnosis.Scheduled dosesof the six agents were the same in the two regimens except for a 30% reduction of every second dose of cyclophosphamidein regimen B. Nevertheless.regimen B resuhed in signiticantly more leukopenic patients, septicemic episode.s,and blood uansfusions, and the dosage of etoposide was more oftcn reduced in arm B lhan in arm A. The increasedtoxicity was not assccialed with improved Vestment results.

Cbemoseasitivity testing of small cell lung cancer using the MTT -Y CamplingBG,Pym J,Baker HM,ColeSPC,LamY-M. OnrarioCancer Treatment andResearch Foundktion. Kingston Regional Cancer Centre, King St West. Kingston, Ont. K7L 2V7. Br J Cancer 1991;63:75-83. A simple calorimetric lest, dic MlT assay, has been adapted for chemosensitivitytestingof human small cell lung cancer cell lines, and fresh lumour samples.Optimal conditionsfor clinical chemosensitivity testingwere determinedusingestablishedSCLC lines. Nineteen differem chemotherapeuticagents were tested, and sixteen of them were found u) be cytotoxic in this assay system. The drug sensitivity of a panel of 16 SCLC cell lines was measured and compared. There were very little intraexperiment varialion, but the interexperiment variation was significant. Cell lines which were derived from patients who had IKNreceived chemotherapyat the lime the cell line was cstablisbedwere more sensitive (to all but one of the drugs) than lines derived from treatedpalients.andtbediffere.nceswerestatisticallysignificantfortwo of the drugs. Gne cell line, NCI-H209. which was derived from an umreated patient. stood out as being the most sensitive or among the most sensitive to all of the drugs tested. Another cell line, H69AR. which is a multidrug resistantsublineof the cell line NCI-H69, was the mostresistamto many of the natural productdrugs tested.Multiple drug chemosensitivitytestingwas performed on eight fresh turnoursamples from SCLC patienls (live pleural effusions. one lymph node. and two primary turnours).It was possibleto perform chemosensirivitylesting on all of the clinical samples in which sufficient tumour cells were available. The drug sensitivity of Ihe clinical samples was, in most cases,within the samerange as for lhe cell lines. Since thisassayis very rapid and simple LOperform, ic may have practical applications in clinical drug sensitivity testing of human mmours.

Circulating hematopoietic progenitors in patients with primary lung cancer Shimizu E, Mukai J-N, Takaue Y. Ogura T. Third Deparlmenl of internal Medicine, University of Tokoshima Schoolof Medicine, 3- 1815 Kuramoto-cho, Tokushima 770. Jpn J Cancer Res 1990;81:1293-9. The levels of circulaling hemalopoielic progenitorswere measured in 28 patients with primary lung cancer. The average numbers of progenitors per millililer of blood were 33 (range O-360) for colonyforming unit-granulocylemacrophage(CFU-GM), 23 (range O-140) for burst-formingunit-erylhmcyte(BFU-E),and4(rangeO-SO)forcolonyforming unit-mixed lineages (CFU-mix). No significant influence of age, sex. histological type, or clinical stage of the tumor on the progenitor levels was de&ted. After cytoreductive chemolherapy of lhepatientsby lrcalrnentwith cisplarinplusetoposide,~becellsshowed 6- to SO-fold rebound overshoots, but no rebound was observed after ueatmem wilh cisplatin alone, cisplacinplus milomycin C or cisplatin plus vindesine plus mitomycin C, or in 4 of 5 patients treated with cyclophosphamideplus adriamycin plus vincrisdne. Peripheral blood hematopoieticprogenitorsshould be useful as an abemative source of stemcells for lung cancer padena vcated with marrow ablative chemotherapy.

Accelerated chemotherapy with or without GM-CSF for small cell lung cancer: A non-randomised pilot study Ardizzoni A. Sertoli MR. Corcione A, PennucciMC, Baldini E, lntra E et al. Division ofPediatric Hematology-Oncology, Istittuo Scientifco G. Gaslini. Genova. Ear J Cancer 1990;26:93741. Two series of five consecutivepatients with small cell lung cancer were treated with an ‘accelerated’ chemotherapy regimen of cyclophosphamide-doxorubicin-vincristine(CAV) and cisplatin-etoposide (FE) alternated possibly every week. In the first group of patients (median age 49 years, range46-52) recombinantgramdocyte.e-macmphage colony-stimulatingfactor (GM-CSF) was given as soonas grade IV leukopenia occurred, while in the secondgroup (median age 59 years, 55-68) no growth factor was administered.The mean interval between chemotherapycoursesand the mean durationof chemotherapywere 10 and 57 days, respectively, in tie patients supported with GM-CSF compared with 13 and 72 days in the control group. One GM-CSF treated patients was withdrawn after the third cycle becauseof severe toxicity. The mean while blood cell and platelet nadirs were 600 and 46OCO/plinIhefirstgroupvs. 840and lOSOOO/plin Ihecomrols.Overall chemotherapydose-intensitywas increasedby two fold in the patients given GM-CSF compared with a 1.5 fold increase in the contml patients. In all cases, irrespective of their treatment. there was an impairedcolonyformingcapacityofcirculatingandmarrow haemopoietic progenitorcells when grade IV leukopenia occurred, with recovery after the end of leukopenia. This pilot study suggestathat accelerated CAV/PE chemotherapy is feasible both with and without GM-CSF. Different GM-CSF schedules as well as combinations of different haemopoieticgrowth factors may further improve dose-intensity. Experimental modelsof regional chemotherapy via the pulmonary artery using cisplatin Rauo GB, Esposito M, Vannozzi M, Fulco RA, Rovida S. Istitttto di Clinica Chirurgica la, Universita di Geneva, Viale Benedetto XV. 10, J-16132 Geneva. Reg Cancer Treat 1990,3:222-7. The pharmacokineticsof cisplatin was investigatedin pigs according 10 tbe infusion mute and administration modality. Twelve pigs were assignedto receive cisplalin (2.5 mglltg) via tie systemicvein, pulmonary artery, pulmonary artery with stop-flow, and pulmonary artery wilh stop-flow/outflow occlusion. Serial blood. lung parenchymaand mediastinalnode &unples were obtained before, at completion of. and 5,15,30,60,120.180, and 240 min after infusion. Urine sampleswere collected 2 hand 2-4 h following drug administration.Specimensfrom thyroid. esophagus.heart, liver, spleen,adrenal gland, kidney and bone marrow were taken 4 h after treatment. Platinum concentrations in plasma, plasma ultratiltrate. erylhrocytes, tissuesand urine were determined by namelessatomic absorptionspectroscopy.Pulmonary artery infusion,with or without stop-flow, yielded no significampharmacokinetic advantage with respect m the systemic vein administration. Instead, pulmonary artery infusion wilh stop-flow/oulflow occlusion

.? and lower syslemicplasma and tissue platinum levels. Ifosfamide,cisplatin, vinblastine combination chemotherapy in the treatment of advanced non-small-cell lung cancer SaitoH,ShimokalaK.Yamamo~oM,SakaH.SakaiS.KawachiHetal. First Department ofMedicine, Nagoya Universiry Schoolof Medicine. Tsurumai. Showa-ku, Nagoya 466. Cancer Chemother Pharmacol 1990;27:251-2. A to~ll of 42 evaluable patients with previously untreatedadvanced non-small-cell lung cancer were treated with a combinationof cisplatin @Omg/m’,day I).vinblasdne (5 mg/m’.days 1 and lS).andifosfamide (1.2g/m*,days l-3). lnall, 1 completeresponseand15pardalresponses were obtained, for an overall response rate of 38% (95% confidence limits, 23.6%54.4%). The median duration of responsewas IS weeks. and the median overall survival was 56 weeks. Toxicity mainly consistedof moderateto severe alopecia in 28 patienls (67%). moderateto severe nausea and vomiting in 27 subjects (64%). and leukopenia comprising< 1,0001eukocytes/mm3in6cases(14%).1na11, 16patienU (38%) had microscopichematuria (WHO grade I), but no hemorrhagic cystitis was documented. Although lhis three-drug combination ap-

273

pears to have moderate cancer, the addition vinblastine

antitumor

activity

of ifosfamtde

against non-small-cell

to the combmatton

did not seem to improve

lung

of cisplatin

and

the response rate.

were compared.

At 30 min after the beginning

blood samples and bronchoscopically taken

for determinations

of platinum

flameless atomic absorption

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: A phase II study of the Northern California Oncology Group Gandara

DR,

Perez EA.

Wold

H, Caggiano

al.l/niversiryofCaliforniaService. Marrinez.

CA 94553.

To investigate small-cell

VAMedicalCenter.

Cancer Chemother

chemotherapeutic

lung cancer (NSCLC),

destgned schedule of high-dose plus mitomycin

V, Malec

C. Between

Pharmacol

we evaluated

March

non-

1987 and March

28&y

cycle)

1989.62

patients

were registered for

a phase II study ofthe Northern CalifomtaOncology

Group

The

(NCOG).

hypertonic

treatment

schedule

saline gtven on a divided

on each day) plus mitomycin

in 6%

(4/61)

(24/61),

34% (IOn9). study were45 enrolled

histologtc

mg/m’per

week (90% of the projected but manageable.

1 .0GiYmm3) and thrombocytopenia toxicity

and clinically

each (13%).

and a peripheral

cases (27%). Improved

treated,

significant

Whether

therapeutic

a randomized

(platelets,

Roizin-Towle

simultaneous

at 30 min. influenced

IO0

plasma

Tumor-tissue by the cisplatin

variability

tn non-small-cell

L. Pirro JP, Hall EJ. Centerfor

University

NY 10032. Radial

College

of plali-

lung cancer.

A lung carcinoma bioreductive

(I Suppl)

the cytotoxic

with

terminal

RSU-1164,

to the aziridine

RB-7040,

substitution

of the alkylating

moiety.

cytotoxicity

in air and hypoxia

with

therapy results in an being evaluated

in

therapy.

RSU-1069

in human

under aerobic

10% cell survival,

A comparison

cells exposed

and rodent

similar results.The cytotoxicity concentrations

that methyl was made

factors, defined

cytotoxicity

of

yielded

to be the ratio of drug

condrtions

were found to be 40,25.

of

to drugs for a 4-h

cells (V-79-379A)

and hypoxic

and

with progressive

of the aerobic and hypoxic

(A-549)

or

and are

RR-88176,andRB-88712.

ring reduced cell killing

period. A direct comparison

in vitro

of nitroimidazoles

in air demonstrated

renal in I7

cultured

rings on the side chain

occurred

in 8 patients

York.

effect of a range of bifunctional

aziridine

of the cytotoxicity

New

S50-S55.

drugs. The drugs tested consisted

nitrofurans

Research,

and Surgeons.

cell line of human orogin (A-549)

alkyl addition

<

Radiological

of Physicians

Res 1990;124

(WBC,

cisplatin

in patients

Studies with bifunctional bioreductive drugs. II. Cytotoxicity assayed with A-549 lung carcinoma cells of human origin

Measurements

trial versus standard-dose

between

concentrations

properttes

in tumor-

ng Pt/mg

suggests a great intcrindividual

designated RSU-1069,

was observed

53.89

seem to be poorly

was used to investigate

in this

Dose-limiting

is currently

dose. This finding

in the 62

developed

this type of dose-intensive

platinum

concentrations

regimen

Leukopenia

sensory neuropathy

index in NSCLC

comparative

squamous,

< 25,OOO/mm’)

respectively. ototoxicity

platinum

was observed

ng Pt/mg tn those receiving

was a weak correlation

dose) and 1.5 mp/

of thts combination

pattents was significant

The

and adenocarcinoma, dose intensities

There

Columbia

(20/61).

subtype included

C delivered

The toxicity

m 3% and 8% of patients

day 1 of the overall

for all patients was 29.3 weeks. The

and mitomycm

(75%).

in 33%

large cell. 31% (4/13);

The median survival

mean cisplating

response,

f

at 30

2.5 mg/m’

100 mg/m’ (1.44 f 0.62

difference

25 mg/m’ vs 51.13 f 65.52

mplm2).

concentrations

in patients receivmg

(22.49

of

in

withacompleteresponsebeingachieved

to reviewed

53% of patients (10/19);

tn’per week

for response analysis,

of cases and a partial

response according

of cisplatin

C given at a dose of 8 mg/m’on

concentrattons

num tumor-diffusion

days I and 8 schedule (100 mg/m’

each cycle. In 61 patients evaluable responseratewas39%

consisted

no significant

by means

The procedure did no1

plasma platinum

than in those receiving

whereas

and tumor-tissue

a pharmacokinetically

(200 mg/m’per

Total

(0.49 f 0.23 pg Wml) pg Pt/ml), receivmg

1990;27:243-7. m advanced

concentrations

lower (P .z 0.01)

infusion,

biopsy specimens were

spectrophotometry.

mitt were significantly

tissue plattnum

ISOMuirRoad,

dose intensity

cisplatin

M, Ahn DK et

induce any comphcation.

of the cisplatin

obtained

which

result in

18, and 8. respectively,

for

thefouragentsRSU-1069,RSU-1164,RB-88172,andRB-881761es1ed

Carboplatin and etoposidc in advanced lung cancer: - A phase I study Liippo

K, Nikkanen

Chemother

Pharmacol

This phase

I study

dose of carboplatin to recommend 100

V, Heinoncn

ofthe

of Dlseaws

E. Deporm~nl

of Turku, Paimto /lospiral,

Chest. Universiry

SF-21540

Preilila.

Cancer

the maximal

tolerated

(Car) together with a fixed dose of etoposide (E) and dose [or a phase II study. The dose of E was

mgfm’given i.v. on days l-3, and the starting dose of Car was 200

mgfm’given toxicity

iv. on day

developed

I. The

dose was escalated until WHO

after two treatment

trial. The maximal tological

tolerated

mg/m’Car.

toxicity

toxtcity

of the combination

Myelosuppression

of WHO

grade 4

cycles in more than one-third

was reached at

was moderate,

grade 4 was encountered

and hema-

in one of live

pattents at 475 mg/m* and in two out of five patients at 500 mg/m*. main

loxic

quency

effects

were

leucopema

of treatment-related

caused by treatment. the plalelet

and thrombocytopenia.

inrections

The fre-

clearance.

overall correlation One complete

betwen

response and

three partial responses were achicvcd after two trcatmentcyclcs. on the results of the present study, the dose of carboplatin with

100 mg/m2eposidc

The

was low and no deaths were

There was a significant

nadtr and creatinine

of

enteredthe

the patients. A total of 33 patients wtth advanced lung cancer a dose or500

given on days l-3)

cells. It has been suggested that under aerobic condittons ring

is primarily

responsible

conditions,

the aziridine

under hypoxic duced 2-nitro

Based

(combined

recommended

for phase II

Sculier Jules

JP, Klastcrsky Bordel,

Pupl

J-L, Cupissol

Service

da

Maladies

1’Aiguelongue. macol

D. Gestin-Boyer Respirarorres.

F-34059

Monfpellrer

C, Bres J. Serrou B, Michel Rue du Major Ceder.

Flandre,

F-B.

(The Netherlands) Two

prospectively

of platinum

Phar-

were studied

in two groups of eight patients who were suffering

advanced non-small-cell cnt schedules of cisplatin

lung cancer. Treatments administration

including

with

a rtet al.,

J, Libert

P et al. Servrce de Medecine, I, B-1000

trials were conducted,

I g/n?; doxorubicin

1.4 mg/m2: all i.v. on day I: every

CAVi

plus vindcsine

3 weeks)

with

or without

was used alone. In 45 cvaluable

wereobserved study, CAVi

(13%;

tericin

was potentiated

B entrapped

might

Among

cisplatin.

as salvage

patients.

6 objective 5.1-20.8).

liposomes

I1 evaluable

Confidence

responses

In thesecond given

consisted of amphomade of egg lecithin,

patients,

Limits:

with

In the first study,

in the molar ratio 4:3:l

resistance

controlled

combination

(cyclo-

vincrtstine

after firs1 lint treatmenl

Ampholiposomes

into sonicated

and stearylamine

overcome

Cancer

with 2 mgfkg of ampholiposomes

not increased. These preliminary encourage

45 mp/m*;

ConfidenceLimitsCL.):

iv.. 24 h prior to chemotherapy. cholesterol

In&u!

Lung

testing the CAVi

(adriamycin)

therapy for small cell lung cancer (SCLC) etoposide

Bruelles.

1990;6: 110-18.

consecutive

phosphamide

(lipid

6 objective

23.4-83.3)

concentraresponses

and toxicity

was

results suggest that ampholiposomes

to chemotherapy

in SCLC

and should

studies.

Chemotherapy or not in advanced non-small cell lung cancer? Cellerino

and plasma concentrations

combined

agent (I.J. Stratford

Hopi@1

Cancer Chemother

1990:27:72-5.

Tumor-tissue

the

whereas

1986).

Rue Heger-Bordet

were observed (55%;

Tumor-tissue and plasma concentrations of platinum during chemotherapy of non-small-cell lung cancer patients

moiety

toxicity,

A phase II study evaluating CA Vi (cyclophosphamide, adriamycin, vincristine) potentiated or not by amphotericin B entrapped into sonicated liposomes, as salvage therapy for small cell lung cancer

tion: 20 mg/ml).

studtes is 450 mg/m’.

for aerobic

motety produces a bifunctional

Br. J. Cancer 53,339-344,

1990;27:229-33.

was carried out to determine

the optimal

in A-549 aziridine

from

two differ-

(25 vs IOU mg/m’on

day 1)

Universira

R. Tummarello di Ancona,

D. Piga

Ospedale

Cancer (The Netherlands)

A. Direfrore

di Ibrrelre.

Oncologia

l-60/00

Clinico,

Ancona.

Lung

advanced

non-

1990:6:99-107.

The value of chemotherapy

(CT)

in patients

small cell lung cancerrcmainscontrovcrsial.

In

with

the past 10yearsresulls