61

cyclophosphamidc 600 mgfm’, cloposldc 100 mg/mzall intmvcnously

day 1-3, cbcry 3 weeks) m a randomlscd trial. 36/54 cvaluable patients

ucatcd wllh CVM achxvcd an ObJccllvc rcsponsc (67%) (95% conti-

dcncc hmlls (CL1 54.79%~) cornpa& witi 44/SO ucatcd with ACE

(88%) (95% CL 80.97%. P = 0.06). For patients wllh hmltcd dlscasc

mcatcd wnlh CVM, 13/17 (83%) (95% CL 64100%) had an objcctlvc

rcsponsc compared wllh 14/15 (Y3%) (Y5W CL 8l-100%) ucaicd wuh

ACE(no1 slgnifican1). Overall median survival was 8 months for CVM and 7 months for ACE. Hacmatologlcal toxiuy was significantly lower

for CVM than ACE and conscqucntly dose rcduclionldclay and mfcc-

lion wcrc ICS with CVM. SuhJCLUvc roxuly was low and alopccla wac

slgnificanlly less for CVM than ACE. CVM IS an act~vc, well tolcratcd new chcmothcrapy rcgm~~ for SCLC.

Pharmacokinetics of bronchial artery infusion of mitomycin in patients with non-small cell lung cancer

Shimuu E, Nakamura Y, Mukal J. Tani K, Yamashu T. Hojo F et al.

NCI-Navy Medical Oncology Branch, Narronal Cancer Insrilure. Be-

rhesdo, MD 20889.510.5. Eur J Cancer 1991;27: 1046-U.

The pharmacokmctics of hronchml artcry mfus~on of 20 mg (I l.4-

14.0 mgfmz) mltomycin was stud& in 14 patients with non-small cell lung cancer (NSCLC). The mean climmation half-lift was 34.3 min

(range h-72). and the arca under UIC plasma conccnuallon-lime curve

(AUC) was 166 ng h/ml (39.312). The mean maximum plasma drug

concentration (C(max)) was 17X @ml (12-540) and hack-extrapolated

plasma drug conccn~a110n was 308 ng/ml(17- 1423). The mean volume

of disulbution in lhc one-compartment model was 0.1X3 I/kg (O.OlO-

0.887) and the rate constant for unchanged drug appearing m the urine

was 1.91/mm (0.57-7.27). Thcrc was considerable variation among

individuals wilh respect LO the pharmacokmctics of milomycm, and the

mean Cfmax) and AUC wcrc Iowcr than those rcportcd after inlravc-

nous admmistmllon.

Randomired trial of cyclophosphamide, doxorobicin, and vincristine

versus cisplatin and etoposide \ersos alternation of these regimens

in small-cell lung cancer

Fukuoka M, Furusc K, Sai~o N. Nlshiwakl Y, lkcgami H, Tamura Te1

al. Deparmwzr of lnwnal Medrcu~e. Osakn Preferrural llahrkrno Ilos~~~ol. J Nad Cancer Ins1 1991;83:855-61.

Bclwccn April 1985 and May 1988, WC conducted a randomued

study comparmg two standard chcmothcrapy regimens with ihc same

regimens glvcn on an allcmating basis in paucn& with small-cell lung

cancer. The patlcnls wcrc randomly a.ss~gncd to rexve cyclophosphamide

al a dose of 800 ms/m2 muavenously (IV) on day 1, doxorubicin at 50

mg/m” IV on day 1, and vincrislmc at 1.4 mg/m’ IV on day I (CAV);

cisplatmat80mg/m*lVonday I andctoposidcat 100mg,/m*IVondays

I, 3, and 5 (PE); or CAV altcmaling with PE (CAV/PE). Each regimen

wan rcpca1cd cvcry 3-4 weeks. Three hundred paticnls wcrc entered in

the sludy, and 288 of lhcm wcrc chgiblc for analysis (97 for CAV, 97

forPE,andW forCAV/PE).Thcrcsponsc rates forPE(78%)andCAV/

PE (76%) wcrc signiflcan1ly hlghcr than 1hc rate for CAV (55%). whde

the complctc rcsponsc r&s wcrc .\lrndar (14%. lb%, and 15%. respcc-

tlvely). Nine (23%) of 39 patients who failed LO respond to the imtial

CAV rcgnncn rcspondcd to PE when they were crossed over. In

COnUasl, only one (8%) of 13 patients responded lo CAV after fading to

respond lo the PE rcgimcn, suggcsung that these two regimens were

parGaIly non-cross-resistant. The rcsponsc duratlon on CAV/PE was

slgnificanlly longer than thal with CAV (P=.OO4). The survival time

with CAViPE (11.8 months) was superior to Ihat with CAV (9.9

months) (P=.O27) or that with PE (9.9 momhs) (P=.O56). In pallems

wl1h hmllcd dlscasc, lhc survival in the altcrnatmg arm was signifi-

canlly superior to the survival in Ihe CAV arm (P=.O14) or the survival

m the PE arm (P=.O23). The LOX~C cffccts wcrc acceptable in all three chcmothcrapy rcguncns. Thcsc rcsulw favor the &mating chcmother-

spy over cilhcr standard chcmothcrapy. such as CAV and PE, although lhc dlffcrcncc? arc not dramatic.

Circumvention of doxorubicin resistance in multi-drug resistant

human leukaemia and lung cancer cells by the pure antioestrogen

ICI 164384

Hu XF, Nadalin G, De Luisc M, Martm TJ, Wakelmg A, Huggins R cl al. Department of Medrcal Oncology, Reparriatron General Ilospilal,

Private Bag No. 1. Ileidelberg WESI. VK 31X1. Eur J Cancer 1991:27:773-

7. ICI 164384, a new steroidal antiocsuogcn, entlrcly devoid of O~SUO-

gcnic activity. modulates doxorublcin resistance in vitro. AI non-

cylolox~c concenuations, ICI 164384 potentialed the cyrotoxicily of doxorubicin in a dose-depcndcnl manner in both the classical multi-

drug resistant (MDR) human lcukacmia ccl1 lines CEM/VLB 100 and

CEMiVLB 1000 and the human small cell lung cancer cell line H69

LX4. ICI 164384 had no cffccton the two respective parental cell lines,

CEM/CCRFand H69P. Noneoftbcsccclllincsexprcsscd theoestrogen

receplor. In comparative studlcs al concentrations ranging from I.25 10 10 pmol/l. ICI 164384 was significanlly more effecove (1.2-6-fold)

than lamoxifcn in reducing the IC,, of doxorublcin in the CEM/VLB

100 line. In rcs~stant cells. ICI 164384 increased ‘H-daunomycin

accumulalion in a dose-depcndcnl manner and was signlfGinlly more

effecuvc than lamoxifcna1conccnlrauonsranging from 2.5 IO IOpmol/

I. ICI 164384 rcduccd !IIC efflux of daunomycin from rcs~stanl cells

more effcctlvcly ihan lamoxfifcn. Thcsc studies suggest 1hac ICI 164384

is an cffcc~~~c modulator of MDR.

Determiningcarhoplatin/etoposidedosage inextensivestagesmall-

cell long cancer (SCLC)

Wolf M. Tesscn H-W, Gocrg C, Achicnath W, Drings P, Havemann K.

Depar~?~nl of lnrernal Medicine. Division of IlemnrologylOncology,

Philipps-Universuy Ilospilols, Baldingersrrasse. D-3550 Marburg. Ann 0x01 1991:2:361-4.

In order IO define the maximum tolerance level of combined ca- bopla1mlcloposidcdosagc.pa1icnls wi1hcxtcnsivestagesmall-celllung

cancer (SCLC) were trcaicd with a fixed dose ofcarboplatm (300 mg/

m* iv on day I) and cscalatmg doses of ctoposldc starting with 80 mgf m2 IV on days l-3. FIX paucnlz wcrc glvcn [his smrtmg and every

following dose level. The dally dose of ctoposldc was mcreased in

incrcmcnls of20 mgJm2 iv un11l scvcrc myclosupprcssion occurred m 3

of 5 pal~cnis. Lcuko- or thrombocytopcma WHO grade 3 or 4 occurred

m O/5 of ihc palicnls a1 the dose lcvcls of 80 and 100 mg/m’, in 114 of

the pat~cnls at the lcvcl of 120 mg/m’, in 2/5 of 1hc patients a1 a level of

140 mg/m’, and 3/5 pat~cms a1 a lcvcl of 160 mg/m’. Thus, incrcasc in

dosage was sroppcd a1 an ctoposldc dose of 160 mg/m’. Olher side

cffccls wcrc mild and consisted prcdominanlly ofnausca and vommng

in 14/25 of 1hc paucms. The overall response rate was 40% with a 12% complelc rcmissIon ra1c. mcdmn survival was 9.3 months and median

progression-free SUWIV~I iotallcd 4.3 months. These rcsul1s rndlcate

that combined carboplalin/ctoposldc is a well rolcratcd rcglmen m

cxlcnsivc-slagc SCLC, with rcsponsc ra1cs comparable 1othosc ofolher

standard pro1ocols. tismg ucaoncnl m~crvals of 4 weeks the recom-

mcndcd dose ofcloposidc in combina1ion with 300 mg/m2carboplalin

was idcnuficd as 140 mg/m’ IV for 3 consccutivc days.

Is cisplatinom-based chemotherapy useful in disseminated non small cell lung cancer? Report of a French multicenter randomized

trial

Quoix E, Dietcmann A, Charbonncau J. Boutin C, Mu-ice JC.Orlando JP et al. Pavilion Lwnnec. CfIRU. BP 426.67091 Srrasbourg Cedex.

Bull Cancer 1991;78:341-6.

The bcnefi1 of chemotherapy for pauents with disseminated non small ccl1 lung canccr (NSCLC) is controversial. The mtmduction of

cisplatinum in 1he combination chemolhcrapy for NSCLC gave rise lo

higher response rates. To study ihc question of le usefulness of cisplalinum-based chemolhcrapy in disseminated NSCLC we con-

duc1cd a prospcc1ivc randomt/cd trial comparing best supportive care 10 vindcsmc + cisplatm. Bc1wccn Dcccmbcr 1985 and March 1988,49

pal~cnls with sugc IV NSCLC wcrc cnrollcd. Ofthc46eliglble palrcnts 24 wcrc in 1hc chcmolhcrapy group and 22 in the bcsl supportive Care group. The 11ca~ncn1 groups wcrc no1 significamly different in lerms of

62

age, performance SILUS, hlslology. Toxictly on the chemotherapy arm

grade 3 or more was observed in 17.5% for ncutropenia. in 8.75% for

vomiting. Thcrc was one death related IO trca~nent. The overall

response rate in the chcmothcrapy group was 41.7%. Patients of the chemotherapy group had a median survival time of 199 days and the

patients of the best supportive cart group had a median survival time of

73 days. The diffcrcncc in survival is highly significant (p < 0.001).

Reversal of cisplatin resistance with amphutericin B in a non-small

cell lung cancer cell line

Morikagc T, Bungo M, Inomala M, Yoshida M, Ohmori T, Fujiwara Y

el al. Pharmacology Division. Nalionol Cancer Cm&r Research Insri- ~ule.S-l-l Tsujiki, Chw-ku. Tokyo 104. Jpn I Cancer Res 1991;82:747- 51.

The potcnliation of anticancer agents by non-anticancer drugs is one of the possible stratcgics for overcoming cellular resistance to chemo-

ticrapy. In order to ovcrcomc cisdiammi~chloroplatinum(II) (CDDP)

resistance, we cvaluatcd the scnsilizing cffccl on CDDP-induced cyto-

loxicity of various non-anticancer agents which might alter membrane

transport. by mcansof a colorimctric [3-(4,5-dimcthyllhiaol-2-yl)-2.5

-diphenyltctruolium bromide] (MTT) assay. Drugs which have previ-

ously been demonwatcd to modify multidrug resistance did not show

a sensitizingeffcct tocisplatin.Onlyamphotericin B (AmB) selectively

conquered CDDP rcsistancc in the CDDP-resistant cell line. A drug

accumulalion study done by the alomic absorption method demon-

strated that the accumulation of CDDP in the resistant cell line recov-

eredtothc levelofthcpa~nlalccll lincaftcrucatmentwilhAmB.Thus.

AmB mightovcrcomcCDDPrcsistance by increasing cheaccumulation of CDDP.