273

pears to have moderate antitumor activity against non-small-cell lung

cancer, the addition of ifosfamtde to the combmatton of cisplatin and

vinblastine did not seem to improve the response rate.

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 V, Malec M, Ahn DK et

al.l/niversiryofCaliforniaService. VAMedicalCenter. ISOMuirRoad,

Marrinez. CA 94553. Cancer Chemother Pharmacol 1990;27:243-7.

To investigate chemotherapeutic dose intensity m advanced non-

small-cell lung cancer (NSCLC), we evaluated a pharmacokinetically

destgned schedule of high-dose cisplatin (200 mg/m’per 28&y cycle)

plus mitomycin C. Between March 1987 and March 1989.62 patients

were registered for a phase II study ofthe Northern CalifomtaOncology

Group (NCOG). The treatment schedule consisted of cisplatin in

hypertonic saline gtven on a divided days I and 8 schedule (100 mg/m’

on each day) plus mitomycin C given at a dose of 8 mg/m’on day 1 of

each cycle. In 61 patients evaluable for response analysis, the overall

responseratewas39% (24/61), withacompleteresponsebeingachieved

in 6% (4/61) of cases and a partial response, in 33% (20/61). The

response according to reviewed histologtc subtype included squamous,

53% of patients (10/19); large cell. 31% (4/13); and adenocarcinoma,

34% (IOn9). The median survival for all patients was 29.3 weeks. The

mean cisplating and mitomycm C delivered dose intensities in this

study were45 mg/m’per week (90% of the projected dose) and 1.5 mp/

tn’ per week (75%). The toxicity of thts combination regimen in the 62

enrolled pattents was significant but manageable. Leukopenia (WBC, <

1 .0GiYmm3) and thrombocytopenia (platelets, < 25,OOO/mm’) occurred

m 3% and 8% of patients treated, respectively. Dose-limiting renal

toxicity and clinically significant ototoxicity developed in 8 patients

each (13%). and a peripheral sensory neuropathy was observed in I7

cases (27%). Whether this type of dose-intensive therapy results in an

Improved therapeutic index in NSCLC is currently being evaluated in

a randomized comparative trial versus standard-dose cisplatin therapy.

Carboplatin and etoposidc in advanced lung cancer: - A phase I study Liippo K, Nikkanen V, Heinoncn E. Deporm~nl of Dlseaws of the

Chest. Universiry of Turku, Paimto /lospiral, SF-21540 Preilila. Cancer

Chemother Pharmacol 1990;27:229-33.

This phase I study was carried out to determine the maximal tolerated

dose of carboplatin (Car) together with a fixed dose of etoposide (E) and

to recommend the optimal dose [or a phase II study. The dose of E was

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

mgfm’given iv. on day I. The dose was escalated until WHO grade 4

toxicity developed after two treatment cycles in more than one-third of

the patients. A total of 33 patients wtth advanced lung cancer entered the

trial. The maximal tolerated toxtcity of the combination was reached at

a dose or500 mg/m’Car. Myelosuppression was moderate, and hema-

tological toxicity of WHO grade 4 was encountered in one of live

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

main loxic effects were leucopema and thrombocytopenia. The fre-

quency of treatment-related inrections was low and no deaths were

caused by treatment. There was a significant overall correlation betwen

the plalelet nadtr and creatinine clearance. One complete response and

three partial responses were achicvcd after two trcatmentcyclcs. Based

on the results of the present study, the dose of carboplatin (combined

with 100 mg/m2eposidc given on days l-3) recommended for phase II studtes is 450 mg/m’.

Tumor-tissue and plasma concentrations of platinum during che- motherapy of non-small-cell lung cancer patients Pupl J-L, Cupissol D. Gestin-Boyer C, Bres J. Serrou B, Michel F-B.

Service da Maladies Respirarorres. Rue du Major Flandre, Hopi@1

1’Aiguelongue. F-34059 Monfpellrer Ceder. Cancer Chemother Phar-

macol 1990:27:72-5.

Tumor-tissue and plasma concentrations of platinum were studied

prospectively in two groups of eight patients who were suffering from

advanced non-small-cell lung cancer. Treatments including two differ-

cnt schedules of cisplatin administration (25 vs IOU mg/m’on day 1)

were compared. At 30 min after the beginning of the cisplatin infusion,

blood samples and bronchoscopically obtained biopsy specimens were

taken for determinations of platinum concentrations by means of

flameless atomic absorption spectrophotometry. The procedure did no1

induce any comphcation. Total plasma platinum concentrations at 30

mitt were significantly lower (P .z 0.01) in patients receivmg 2.5 mg/m’

(0.49 f 0.23 pg Wml) than in those receiving 100 mg/m’ (1.44 f 0.62

pg Pt/ml), whereas no significant difference was observed in tumor-

tissue plattnum concentrattons (22.49 f 53.89 ng Pt/mg in patients

receivmg 25 mg/m’ vs 51.13 f 65.52 ng Pt/mg tn those receiving IO0

mplm2). There was a weak correlation between simultaneous plasma

and tumor-tissue platinum concentrations at 30 min. Tumor-tissue

platinum concentrations seem to be poorly influenced by the cisplatin

dose. This finding suggests a great intcrindividual variability of plali-

num tumor-diffusion properttes tn non-small-cell lung cancer.

Studies with bifunctional bioreductive drugs. II. Cytotoxicity as- sayed with A-549 lung carcinoma cells of human origin Roizin-Towle L. Pirro JP, Hall EJ. Centerfor Radiological Research,

Columbia University College of Physicians and Surgeons. New York.

NY 10032. Radial Res 1990;124 (I Suppl) S50-S55.

A lung carcinoma cell line of human orogin (A-549) cultured in vitro

was used to investigate the cytotoxic effect of a range of bifunctional

bioreductive drugs. The drugs tested consisted of nitroimidazoles or

nitrofurans with terminal aziridine rings on the side chain and are

designated RSU-1069, RSU-1164, RB-7040, RR-88176,andRB-88712.

Measurements of the cytotoxicity in air demonstrated that methyl and

alkyl addition to the aziridine ring reduced cell killing with progressive

substitution of the alkylating moiety. A comparison was made of

cytotoxicity in air and hypoxia with cells exposed to drugs for a 4-h

period. A direct comparison of the aerobic and hypoxic cytotoxicity of

RSU-1069 in human (A-549) and rodent cells (V-79-379A) yielded similar results. The cytotoxicity factors, defined to be the ratio of drug

concentrations under aerobic and hypoxic condrtions which result in

10% cell survival, were found to be 40,25. 18, and 8. respectively, for

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

in A-549 cells. It has been suggested that under aerobic condittons the

aziridine ring is primarily responsible for aerobic toxicity, whereas

under hypoxic conditions, the aziridine moiety combined with a rt-

duced 2-nitro motety produces a bifunctional agent (I.J. Stratford et al.,

Br. J. Cancer 53,339-344, 1986).

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 Sculier JP, Klastcrsky J, Libert P et al. Servrce de Medecine, In&u!

Jules Bordel, Rue Heger-Bordet I, B-1000 Bruelles. Lung Cancer

(The Netherlands) 1990;6: 110-18.

Two consecutive trials were conducted, testing the CAVi (cyclo-

phosphamide I g/n?; doxorubicin (adriamycin) 45 mp/m*; vincrtstine

1.4 mg/m2: all i.v. on day I: every 3 weeks) combination as salvage

therapy for small cell lung cancer (SCLC) after firs1 lint treatmenl with

etoposide plus vindcsine with or without cisplatin. In the first study,

CAVi was used alone. In 45 cvaluable patients. 6 objective responses

wereobserved (13%; ConfidenceLimitsCL.): 5.1-20.8). In thesecond

study, CAVi was potentiated with 2 mgfkg of ampholiposomes given

iv.. 24 h prior to chemotherapy. Ampholiposomes consisted of ampho-

tericin B entrapped into sonicated liposomes made of egg lecithin,

cholesterol and stearylamine in the molar ratio 4:3:l (lipid concentra-

tion: 20 mg/ml). Among I1 evaluable patients, 6 objective responses

were observed (55%; Confidence Limits: 23.4-83.3) and toxicity was

not increased. These preliminary results suggest that ampholiposomes

might overcome resistance to chemotherapy in SCLC and should

encourage controlled studies.

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

Cellerino R. Tummarello D. Piga A. Direfrore Oncologia Clinico,

Universira di Ancona, Ospedale di Ibrrelre. l-60/00 Ancona. Lung

Cancer (The Netherlands) 1990:6:99-107.

The value of chemotherapy (CT) in patients with advanced non-

small cell lung cancerrcmainscontrovcrsial. In the past 10yearsresulls