206

Phase 11 study of high-dose epirubicin in untreated patients with small-cell lung cancer Macchiarini P, Dancsi R, Mariotti Ret al. Service of’Fhoracic Surgery, University of Pisa, Vu Rem. 67, I-56100 Piss. Am J Clin Oncol Cancer Clin Trials 1990;13:302-7.

Eighteen previously untreated patients with histologically confirmed small-cell lung cancer were treated with high-doseepirubicm (course I, 100 mg/m? courses 2-6, 140 mg/mz, day 1) every 3 weeks. Overall response rate was 33% (95% confidence limits, 14-52%), including two complete and four partial responses. The response rates for limited (n = 11) and extensive (n = 7) disease patients were 45% and I4%, respec- tively. With a median follow-up of 18 months, estimated 2-year survival of all patients was 29% and the median duration of response 18.5 months. The dose limiting toxicity was myelosupprcssion, with a median granulocyte nadir of l,150/mm3, 39% of patients had neu- tropenicfevcr. NauscJvomiting,alopecia,andstomatitis were themost common nonhematological toxicities, usually mild to moderate. Acute cardiac toxicity was unusual and no episodes ofcongestive heart failure were observed. Cumulative doses of 800 mg/m” were associated wilh moderate cardiotoxicity (grade 2), as assessed by endomyocardial biopsy and electron microscopy analysis. These results indicate that epirubicin, at the present doses and schedule, is an active single agent in patients with small-cell lung cancer, with acceptable general and moderate cardiac toxicity.

Current results of chemotherapy in non-small cell lung cancer Fukuoka M, Negoro S, Takada Met al. Deparmenr oftnternat Medi- tine. Osaka Prefeclural ttabikino Hospital andNariona1 Kinki Central Hospilal, Osaka Jpn J Thorac Dis 1990;28:203-9.

From 1983 to 1988, two prospective randomized studies were con- ducted in the treatment ofpauents with inoperable non-small cell lung cancer(NSCLC), The first was a comparison of cisplatin (CDDP) alone vs CDDP plus vindesine (VDS) (CV-I), and the second was the comparison of CDDP plus VDS (CV-2) vs CDDP plus VDS plus mitomycin (MMC) (CVM) vs CDDP plus etoposide alternating with VDS plus MMC (CE/VM). A total of 345 patients entered mto these two studies were evaluated. The response rates were 9.3% for CDDP alone, 26.8% for CV-1,33.3% forCV-2,42.6% for CVM, and 19.1% forCE/ VE. ThereweresignificantdifferencesinresponseratesbetweenCDDP alone and CV-I (p < 0.01) and CVM and CEiVM (p<O.Ol). No differences wcrc observed in the durations of response and survival among the five treatment arms. Females responded to chemotherapy better lhan males, and squamous cell carcinoma responded better than adenocarcinoma. Sex. performance status and stage were significant as prognostic factors in advanced NSCLC patients. Responders to chemo- therapy live longer than nonresponders. In conclusion. CVM is consid- ered to be currently best available regimen. No survival benefit has been proved for any treatments for advanced NSCLC. Chemotherapy for NSCLC is still investigational.

Chemosensitivity test for lung cancer Nishio K, Saijo N. Pharmacology Division, National Cancer Research Insriture, I-l, TsukijiS-chome, Chuo-Ku, Tokyo 104. Jpn J Thorac Dis 1990;28:225-31.

The complete response rate in advanced non-small cell lung cancer

is extremely low and the effect of chemotherapy on survival is still obscure. The emergence of resistance to anticancer agents results in the poor prognosis in small cell lung cancer although the initial response rate has improved. The significance of chemosensitivity test in lung cancer can be classified to three areas. The first of these as the individualizationofchemotherapy, which meanstheselectionofdiffer- ent active drugs for individual patients. In spite of numerous studies, there remain many theoretical and technlcal problems in predictive drug sensitivity testing. It is still far from practical use. Secondly, drug sensitivity tests have contributed to the screening of new anticancer agents. Since 1986, NC1 (USA) started the disease oriented drug screening system (DOS) using human cancer cell lines. So far, active drugs against drug resistant tumors such as colon and non-small cell carcinoma have been found out by DOS. The clinical application of these drugs selected by DOS may give the answer concerning the

validity of this new screening system. Thirdly, drug sensitivity tests have widely been used for the analysis of the mechanisms of drug sensitivity and resistance. By the progress of study in this field the biochemical and molecular biological targets of drug sensitivity te.st will be elucidated.

Characterization of an etoposide-resistant human small-cell lung cancer cell line Minato K, Kanzawa F, Nishio K, Nakagawa K, Fujiwara Y, Saijo N. Pharmacology Division. National Cancer CenlerResearchtnsrirIrle, I- I TsukijiS-chome, Chuo-ku, Tokyo 104. Cancer Chemother Pharmacol 1990;26:313-7.

We established an ctoposide (VP-16)-resistant human small-cell lung cancer line (H69/VP) by stepwise exposure to VP-16. The resis- tance of H69M’ to VP-16 was 9.4-fld that of the parent cell line (H69/ 0 H69/VPshowed cross-resistance to Adriamycin (ADM), (4Q-4.1 I- diethyl-4-hydroxy-9-[(4-pipcridinopiperidino)carbonyloxy]-lH- pyrano[3’,4’:6,7]indolizino [1,2-blquinoline-3,14(4H,lZH)-dionehydm- chloride trihydrate (Cm-1 I), teniposide (VM-26), vindesine (VDS) and vincristine (VCR). The amount of DNA topoisomerase II (topo.11) was nearly the same in H69/P and H69iVP cells. The catalyuc activity of topo.11 in H69/VP cells was lower than that in the H69/P line.

Accumulationof [‘HI-VP-16in H69/Pwas6.1-7.5 timeslowerthan that

in H69/F’. According to Northern blot analysis, the mdr-1 mRNA level in H68/VP was markdely higher than that in H69/P. These findmgs suggest that H69/VP has a typical multidrug resistance (MDR) pheno-

type and that alteration of the drug accumulation mediated by P-

glycoprotein may play an important role in resistance to VP-16. Reduced topo. II activity may also be associated with VP-16 resistance.

Pharmacokinetics and toxicity of hvo modalities of etoposide info- sion in metastatic non-small-cell lung carcinoma Chatelut E, Chevreau C, Blancy E et al. Deparmnenf de Biologic Clinique, Cemre ClaudiusRegaud, 20-24 Rue du Porn Saint-Pierre, F-

31052 Totdouse Cedex. Cancer Chemother Pharmacol1990;26:365-8. The pharmacokinetics and toxicity of two schedules of etoposide

administration were studied in 19 patients suffering from metastatic non-small-cell lung cancer. Ten subjects received a 12-h continuous venous infusion (CVI) of 360 mg/m’etoposide, and nine were given a daily dose of 120 mg/m* for 3 consecutive days. In the two groups 80 mg/m’cis-diamminedichloroplatinum (II) (CDDP) was infused on day 1. With CVI, the steady-state plasma concentration was reached 12-24 h after the start of the treatment. The plasma elimination rate showed a biexponential decay curve in both groups. No significant difference between total body clearance and the B-phase volume of distribution was noted between the two modalities of administration. No relation- ship was found between biological and pharmacokinetic parameters.

Phase II study of carboplatin in untreated, inoperable non-small- cell lung cancer Gatzemeier U, Heckmayr M, Hossfeld DK, Zschaber R, Achterrath W, Lenaz L. Bristol-Myers Squibb Company, 345 ParkAvenue. New York, NY 10154. Cancer Chemother Pharmacol 1990;26:369-72.

A total of 51 previously untreated patients with non-small-cell lung

cancer (NSCLC) were treated with 130 mum2 carboplatin given every

4 weeks as an i.v. infusion on days I, 3, and 5. Ten patients achieved a

partial response and live, a minor response. The overall response rate

was 20% (95% confidence limits, 8%-32%). The median duration of

response was 3 months and the median overall survival was4.5 months.

Leucopenia, thrombocytopenia and anemia of WHO grade 3 occurred

in 4%.6% of patients and grade 3 nausea and vomiting was observed in 8% of our subkts. Grade 4 thrombocytopenia occurred in 3 (6%) patients. Apart from nausea and vomiting, nonhematologic toxicities

above grade 2 were not observed. Further trials using carboplatin in

NSCLC as a single agent or in combination with otherchemotherapeu-

tic agents or radiation are warranted.

Cisplatin, ifosfamide and vindesine in the chemotherapy of non- small-cell lung cancer: A combination phase II study Honda R. Fujita A, Inoue Y, Asakawa M, Suzuki A. Deparmuwf of tnternal Medicine, Section 3, Sapporo Medical College, South-l Wesf-

207

16, Chuoku. Sapporo 060. Cancer Chemolher Pharmacol 1990;26:373-

6.

A tol;tl of 47 patients with unresectable non-small-cell lung cancer

weretrcmed witharcglmen conslstmgofwplatin (CDDP. lOOmg/m),

lfosfamide(IFX,2g/m*x 3; with mcsna)andvindesine(VDS,3 mg/m’)

(CIV). Tlus regimen was given over a 3. or 5.week period. Among 40

completely cvaluable patienB, 19 partial responses (PRs) were ob-

wved,forarcsponseratcof47.5% (78.6% insquamous-cellcarcinoma

and 30. I B in adeno-and large-cell carcmoma); no complete responses

(CRs) were ohtamed. The hcmatologic toxicity was not severe, but the

renal toxicitywasrather high;twopatwnlsdevelopedacuterenal failure

and died of subsequentpancytopcnla and sepsis. We concluded that the

CIV rcglmen was more effective, especially agamst squamous-cell

carcinoma, but more toxic than the combination of CDDP and VDS for

non-small-cell lung cancer and rhat candidates for ihis therapy must be

carefully chosen.

Quality of life assessment during chemotherapy for non-small cell

lung cancer

Maasiha PK, Raulonen JK, Mattson MT, Mattson KV. Deparrmen! of

PulmonaryMedicine.Ijelslnki L~niversiryCen~ralllospilal,Ilaartman-

uduztu 4. 00290 Ilelsinki. Eur .I Cancer 1990:26:706-8.

Quality of hfc was assessed by linear analogue scales for patients

wth non-small cell lung cancer parliclpating m a phase I-II trial.

Chcmothcrapy consisted of cyclophosphamide 600 mg/m’ intrave-

nously on day 1 and uimctrexatc (five dose levels) intravenously on

days 1 -S, repealed every 21 days. Elcvcn subjective items wereassessed

hy the patmnts. Nme of the scales related to performance, problems

related to the disease itselfand uncertainty about the value of ueatmcnt:

two scales relalcd LO the major known side-effccls of chemotherapy.

Each paticm completed the scales before treatmcnt, on the last day of

treatment (day 5) and once bctwccn cycles. Variatron in the scores for

Items (e.g. for nausea or appetite) suggests that the method was useful

m estimating the patlem’s perceived quality of life during repeated

cycles of chemotherapy. Compliance was good and the method was

easily accepted by both patients and nurses as part of a routine.

Aerosol application of interferon-alpha in the treatment of bronchi-

oloalveolar carcinoma

Van ZandwiJk N, Jassem E, Dubbclmann R, Braat MCP, Rumke P.

Departmew of Medical Oncology, The Nelherlands Cancer Inslrlule,

Piesmanlaan 121.1066 CXAmsu~dum. Eur JCanccr 1990:26:738-40.

IO patients with locally advanccd bronchioloalvcolar carcinoma

were treated with interferon-alpha as an inhaled aerosol. Imtial doses

ranged between 1 and 10 MU dally or thrice weekly and were then

increased to 20 MU dally. Trcalmcnc was contmued until dwase

progression or exccssivc loxlctly occurred. 9 pauents wcrc evaluable

for toxlcrty. In 1 case ucatmcnt had to bc slopped after 2 weeks due (0

fever, fatigue and progressive dyspnoea. 2 patients developed fever, 1

had malaw, fatigue and loss of appctltc and 2 had dose-dependent

transient dyspnoea. According to standard criteria no turnour responses

could be detected. In 6 out of 8 evaluated for response Lo interferon,

radiological stabilisauon of dlscase for 7-43 weeks (me&an 15) was

observed. These resulu poml LO the fcasibihty of aerosol inhalauon of

mtcrferon-alpha, but also to its hmlted antitumour actiwty m locally

advanced bronchioloalveolar carcmoma.

Effect of inhaled natural interferon-alphaondiffuse bronchioalveo-

lar carcinoma

Kmnula V, Camel1 K, Mat&on K. Deparrmem ofFulmonory Medicine. Helsmki Univerwy Cenrral Ijospilal, llaorlmaninkalu 4,00290 IMsinki.

Ear J Cancer 1990;26:740-1.

Six patients wilh diffuse bronchloalveolarcarcinoma confined Lo the

thorax were treated with mwrferon-alpha by inhalation. The dose was

1 or 6 MU thrice daily. Therapy was continued unld the tumour

progressed or bronchial hyperreactwlty became unacceptable. The

treatment was not effective.

A pilot study with aa ifosfamide, carboplatin and etoposide regimen

(ICE) in patients with advanced non-small-cell lung cancer

Scalier JP, Bron D, Sergysels R, Klaslersky J. Clinique des V&s

Rrsprratorres. lloprral Sami-P~rre. Universite Libre de Bruxelles.

Drug Invest lYYO;2:31-7.

A phase I study wth Ihe combmation of lfosfamidc + carboplatm +

ctoposide (ICE) was conducted in patients with advanced non-small-

cell lung cancer (NSCLC). Patients who had had prcwous therapy wcrc

given tic following dosages: ifosfarmdc 2 g/m’ on days 1 to 3,

carboplatin 75 mg/m”on days 1 and 2, and ctoposidc X0 mg/m’on days

1 and 2. In those with no prcviow Ihcrapy, carboplatm 75 mg/m’ was

admimstered on days 1 IO 3. In 15 treated patients, 3 objectlvc responses

were documcmcd, all from the 7 patients wllh no prior therapy. The

dose hmiting toxicity was Icucopema. A phase II study IS required to

dctermmc the exact activity 01. the combmatlon m patients wth ad-

vanced NSCLC. Two paficnts wth hmitcd NSCLC wcrc ueatcd wth

high doses ICE (ifosfamlde 6 g/m2 on day I ; carboplatm 400 mg/m* on

days 1 and 2, and etoposidc 500 mg/mt on days I and 2) and autologous

bone marrow mfusion followed by local Lhcrapy. Toxuty was acccpt-

able. Responses wcrc of short duration (IO months) and both patrcnts

died 11 and 15 months, rcspcctlvcly, after the start of Ihcrapy.

The use of clonogenic assays in assessing the response of human lung

cancer cell lines to a and gamma interferons alone or in combina-

tion with adriamycin

Jabbar SAB, Twentyman PR. Medual Rrsearch Councd. C/mica1

Oncology and Radiorherapeuucs Unir, /fills Road. Camhrldge CB2

2Qll. Int I Cancer 1990;46:546-51.

The antiproliferative and cytotoxic effects of purlfxxi IFN-a and

recombmam IFN-gamma were mvcstigatcd usmg both duect cell

counting and aclonogcnic assay on a panel of 5 eslabhshcd human lung

cancer cell lmes and for 2 of them also on thcu muludrug-rwslant

counterparts. There was considerable hclerogcmxy m the response of

thecclllincstothcIFNsm termsofgrowthinhibitlon. Clonogcmcassay

of IFN-treated cells indlcatcd that, where a cell lme had responded

markedly 10 an IFN, only a small fractmn of the cells remammg after

IFN lreatmcnt were clonogemcally wablc. When cell\ wcrc placed mto

the clonogcmc assay m the prcscncc of IFNs, the t~mc course of colony

formation was diffcrcnt from that seen in the control culturca for mosL

of the cell lines. The measured ‘surviving fracuon’ was greatly depend-

ent upon the time of colony counting. When the effcct~ of IFNs in

combination with ADM were studied, conclusions regarding the mtcr-

action of the effects of Ihe agents also depended upon the tlmc at which

colomcs were counted.

A randomized study comparing cisplatin or carhoplatin with eto-

poside in patients with advanced non-small-cell lung cancer: Euro-

pean OrgaoizHion for Research and Treatment of Cancer Protocol

07861

Klastcrsky I, Sculicr JP, Lacrolx H CL al. lnslirur ./ule.\ Border. Rut,

/je#er-Border I. 1000 Brurlies J Clm Oncol lY9O;X: 1556.62.

The European Organuatmn for Rcscarch and Trcatmcnt of Cancer

(EORTC) Lung Cancer Working Party conducted a randomI& trial

comparmg c~splatin (CDDP: I20 mg/m*, day 1) and carboplatm (CBDCA:

325 mg/m*, day I) m combmatlon wth cloposldc (VPlh: 100 mg/m2,

days I, 2,and3) madvanccdnon-small-cell lungcanccr(NSCLC).Two

hundred twenty-eight patients wcrc chglble for saw& and 202assess.

able for rcsponsc. WC obtamed 27 of 100 objcctivc rcsponscs (ORs;

27%) m the CDDP arm and 16 of 102 (16%) in the CBDCA arm (p =

.07). Thcrc was no slgnifxant difference m survival. Toxuty, consIs1-

mg mainly of myclosupprewon and renal functmn Impairmcm, was

sigmficamly increased m the patients rcccwng the CDDP ucauncnt.

Wcconcludc IhatCDDPplus VPl6wasmorcaclwe bulalsomorc toxic

than CBDCA plus VP16 in advanced NSCLC.

Non-P-glycoprotein mediated mechanism for multidrug resistance

precedes P-glycoprotein expression during in vitro selection for

doxorobicin resistance in a human lung cancer cell line

Baas F, Jongsma APM, Broxterman HJ ct al. Divisron of Molecular Bwlogy, TheNeiherlands Cancerlnsliiute. Pla.wumlann 121,1066 CX

Amverdam. Cancer Rcs 1990;50:5392-8.

Two dlffercnt mechanisms lhat contrlbutc to muludrug resistance

(MDR) were found m dcrwatives of the human squamous lung cancer cell line SW-1573. The parental ccl1 lmc has a low amoum of mdrl P-