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 Ram. 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-