Abstracts /Lung Cancer 12 (1995) 265-329

disease interval and long survival of patients submitted to continuous OCT therapy will be strictly monitored. Interesting was the observation that patients in whom basal NSE lowered more than 25% at?er the first cycle of OCT seemed the most benefitted candidates by synergic treatment. The interpretation of the deerease of NSE under OCT could be correlated to the presence of receptors for somatostatin in tumor tissue, as already shown by Lambmts in 1989. Evidently the presence of the reeeptors points out a higher differentiation of NE tissue, and then oscillations of the NSE value during the therapy with OCT higher than 25% Can express a better prognosis of the tumor. We are planning to carry out a polyccntric randomized trial comparing chemotherapy versus OCT plus chemotherapy.

Cisplatia and etoposide verses cyclopbosphamide, epirobicin and viocristine in small cell lung cancers A randomised study Vemncsi A, Cartei G, Crivellari D, Magri MD, Della Valentina M, Foladore S et al. Service of Oncologv. General Hospital, Gorisia. Eur J Cancer Part A Gem Top 1994.30: 1474%.

From September 1986 until December 1991, 139 patients with histologically-proven small cell lung cancer, age < 75 years, perfom~ancc status > 40, absence of brain metastaz and no previous treatment, were random&d to receive either CEV cyclophosphamidc 1000 mglm’ intravenous (i.v.), cpirubicin 70 mg/m’ i.v., vincristinc I .2 mg/m’ i.v., every 3 weeks or PE (cisplatin 20 mg/ml iv. and ctoposidc 75 mg/m’ i.v. for 5 consecutive days, every 3 weeks) for six cycles. AtIer three cycles, responding patients received radiotherapy to the chest (45 Gy/15 sessions) and to the brain (30 Gy/lO sessions - only in patients with limited disease achieving complete remission). 3 patients were ineligible. Patient characteristics included (CEVIPE) total number 66/70, median age 60/61 years, median performance status SO/SO, extended-disease 33148 cases (P = 0.04). In cvaluable patients, 42162 (67.7%) responded to CEV while 42158 (72.4%) responded to PE (P = non-significant), respective complete response rates were 16.1 and 29.3% f.P = non-signiticant) and respective complete response rates in patients with extended disease were 9.4 and 28.9% (P = 0.03). Median survival was 10.5 months, without significant differences in the two treatment arms, even after adjushncnt for stage. PE was less well tolerated than CEV Although PE is more active then CEV in certain subsets of patients, its apparent inability to improve survival in this and in other shrdies questions its routine use in small cell lung cancer.

Low-dose chemotherapy delays lrlapac of a dominated and resistant satb-popuiationinabe6erogeneous bUmrnSCLCINOgNftlItItOdemioe Aabo K, Vindclov LL, Christensen IJ. Spang-Thomsen M. Univ. lnsfilule Palhologieal Ana~onry, Universiry Copenhagen, Fredm.k d. Vb Yj II, DK- 2100 Copenhagen. Int J Canwr 1994;59:394-9.

We investigated the influence of cellular heterogeneity on the response to lowdose BCNU chemotherapy of an artif&lly mixed human sm&cell lung cancer (SCLC) xcnogratI in nude mice containing a BCNU-sensitive and dominating sub-population and a BCNU-resistant and undetectable (dominated) sub-population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry @X4). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low-dose trcstments with BCNU or no treatment. Afbz s further 3 to 4 weeks, a highdose treabncnt (LD,d was given to both groups of treated tumors. Changes in the relative pmportions of and cell lines in the tumors were measured by FCM on tine-needle tumor aspirates. At the time of low-dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response w.ss seen afier low-&se treatment. After the high-dose treatment, a similar short response was seen. In the non treated group, the sensitive cells continued to dominate. At the time of tumor regrowth atIer the lowdose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression atIer the response to the high-dose treatment, the resistant cell line was the predominant population. Jf compared with a single high dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing subpopulation influenced the outcome of the treatment.

Etoposkhduced cell cycle delay aod arrest-dependeot modhtioo of DNA topoisomerase 11 io smallseli long cancer cells Smith PJ, Soucs S, Gottlieb T, Falk ST, Watson JV, Osborne RJ et al. MRC Cene~. Cambridge CB2 2QW. Br J Cancer 1994,70:914-21.

AS an approach to the rational design of combination chemotherapy involving the anti~anocr DNA topoisomemse II poison ctoposidc (VP-16), we have studied the dynamic changes occurring in smallccll lung cancer (SCLC) ccl1 populations during protracted VP-16 exposure. Cytometric methods were used to analyse changes in target enzyme availability and cell cycle progression in a SCLC cell line, mutant for the tumour-suppmsor gene p53 and defective in the ability to arrest at the G,/S phase boundary. At concentrations up to 0.25 iM VP-16, cells became arxsted in G, by 24 h exposure, whereas at coneentmtions 0.25-2 iM Gz arrest was preceded by a dose-dependent early S-phase delay, confirmed by bromodcoxyuridine incorporation. Rccovcry potential was determined by stathmokinctic analysis and was studied further in aphidicolin-synchronised cultures released from G,/S and subsequently exposed to VP-16 in early S- phase. Cells not experiencing a VP-16-induced S-phase delay entered G, delay dependent upon the continued presence of VP-16. These cells could progress to mitosis during a 6-24 h period after drug removal. Cells experiencing an early S-phase delay remained in long-term G, arrest with greatly reducing ability to enter mitosis up to 24 h atIer removal of VP-16. Irreversible G, arrest was delimited by the induction of significant levels of DNA cleavage or fragmentation, not associated with overt apoptosis, in the majority of cells. Westem blotting of whole-cell preparations showed increases in topoisomerase II levels (up to 4- fold) attributable to cell cycle redistribution, while nuclei from eells recovering from S-phase delay showed enhanced immunorcactivity with an anti- topoisomerase II6 antibody. The results imply that traverse of G,/S and early S- phase in the presence ofa specific topoisomerase 11 poison gives rise to progressive low-level trapping of topoisomemse II& enhanced topoisomerase II6 availability and the subsequent irreversible arrest in G, of cells showing limited DNA fragmentation. We suggest that protmeted, low-dose chemotherapeutic regimens incorporating VP-16 are preferentially active towards cells attempting G,/S transition and have the potential for increasing the subsequent action of other topoisomcrase II-targeted agents through target enzyme modulation. Combination modalities which prevent such dynamic changes occurring would act to reduce the cffeetivencss of the VP-16 component.

Effects of somatostatio analogue RC-160 and bombesin/gastrin- releasing peptide antagooists on the growtb of boman small-cell and nooamalkell long carciwmas in nude mice Pinski J, Schally AV, Halmos G, Szcpcshti K, Gmot K, O’Byme K et al. VA Medical Center; 1601 Perdido S&m& New Orleans, U 70146. Br J Cancer 1994;70:886-92.

We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung eareinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenogratls of the SCLC NCI-H69 line or non-SCLC NCI-HI 57 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bornbe& GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 ig per animal per day, inhibited the growth of H69 SCLC xenogmt?s as shown by more than 70% reduction in turnour volumes and weights, as compared with the control group. BombesinIGRP antagonists, RC-3440, RC-3095 and RC- 3950-Q given S.C. peritumorally at a dose of 20 ig per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-B had the greatest inhibitory et&t and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xcnogratts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearingeithcrtumour model,administration ofRC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 turnours, but not on non-SCLC HI57 tumours. Receptor analyszs demonstrated high- affbdty binding sites for epidcmnl growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and HI57 turnours. EGF receptors were down-regulated on H69 tumoursat%x treatment with RC-160 and bomb&n/ GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 htmours was decreased after treatment with RC-160, but bombcsinMjRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/

Abstmcis/ Lung Cancer 12 (1992) 265-329

GRP antagonists inhibit the growth ofH-69 SCLC, but not ofH-157 non-SCLC xcnogr@.f?~ in nude mice, whereas somatostatin snalogue RC-160 is effective in both tumour models. This raises the possibility that thcsc peptide analogues could be used selectively in the treatment of vsrious subc%sscs of lung cancer.

Compmisoo de&t afLY ciqhtin (DDP) with Iv. carboplatia (CDP) in the treatment of advanced lung cancer under maximum tolerance ~0 Hua X-M. Deporbnmt of Thomcic Swge~, Jilin Provincial Cancer Hospital, Changchm. Chin J Clin Oncal l994;21:621-4.

A comparison of cffccts of DDP 100-120 mp/ml and CDP 400450 mp/ml WBS put in trial. The combination probxols used were the same, i.e. (1) ADM 60-80 mg (IO cases), VP-16 100 mg x 5 (100 cases), (2) VP-16 200 mg Y 5 (3 casts), (3) in addition to (1) was added Mcthylene Blue 400 mg x 3 (1 cast). 14 patients with late lung cancer with similar histologic type and clinical stage wcfc tnxtcd. The overall remission rates in DDP and CDP group were 78.5% and 57.1% respectively. Severe drug toxicities wcrc obscrvcd in l/3 of the patients. It is shown that DDP was superior to CDP under MTD regimen, especially for NSCLC patients.

Dose-fmdiog study of parlitorel (Thud) plus cisplatia in patients with aoa-small cell lungcaocer Klastcrsky J, Sculier p. Deparbnenl of Medicine, Institut Jules Bordef, I Rue Heger-Borde,: 2000 Brussels. Scmin Oncal 1994,21:Suppl S39-43.

We pnscnt preliminary results of a study undatakcn in previously untreated patients with non-small cell lung cancer to dctcnninc the maximum tolerated dose of paclitaxcl (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered as a 3-hour intravenous infusion in combination with cisplatin every 3 weeks; to cvaluatc the nature, frequency, scvcrity, and duration of adverse events associated with this drug combination; and to cvaluatc the combination’s anti-tumor ctlicacy. Thus far, we have treated 10 patients with cisplatin (100 mp/m’) and increasing doses of paclitaxel(l35, 170, and 200 ms/m*). Among nine evalwble patients, four partial responses have been obtained, disease in three patients progressed at&r three courses, and no changes wcrc seen in one patient. One patient had two cardiac arrests within 8 days of the onset of therapy, from which he recovered; he died I month later of massive hcmoptysis. Thrombocytopcnia was not seen in these patients, and neutropcnia (<I,000 grsnulocytes/iL) was seen in only thm patients. Infections were seen in three patients and wcrc manageable in all casts. Other toxicities consisted mainly of World Health Organization grades Il and III alopecia and nausea and/or vomiting. No grade III nephrotoxicity, ncurotoxicity, hypersensitivity, mucositis, or infection was seen in this series after one to three courses of chemotherapy, one patient presented with grade IV cardiotoxicity 6 days at&r the onset of therapy. So far, the maximum tolerated dose of the cisplatin/paclitaxel combination has not been reached; however, dclinitive conclusions await the full treatment of additional patients. Moreover, the possibility of cumulative and delayed toxicity must be evaluated eflcr B sufficient duration of follow-up in adequate numbers of patients.

Prelimmary re*wltclottwo~mdingJtudiesoCprlitnrel~~ol) and carboplatia in non-small cell lung and ovarian eancen: A European cancer centre effort Giaccone G, Huizing M, Huinink WTB, Koolen M, Postmus P, Van Kralingen K et al. Deporbnmr of Oncolow, Free Universi~ Hospital, De Boelelaan 1117, HV 1081 Amsterdam. Semin Oncol 1994,21:Suppl 8:34-g.

Paclitaxcl (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, and cartoplatin have activity in advanced non-small cell lung cancer (NSCLC) end ovarian cancer. Two dose-finding studies wcrc initiated to identify the optimal doses for the paclitaxcVcarboplatin combination when paclitaxel is given in a 3-hour infusion. The fact that the pharmacologic intaction between paclitaxcl and cisplatin increases the toxicity of paclitaxel when cisplatin is given before it also prompted an investigation ofthc influence of drug sequence on toxicity and pharmacokinctics in the NSCLC trial. Thirty-three patients with advanced NSCLC and II with advanced ovarian cancer previously untreated by chemotherapy have been enrolled to date. In the NSCLC trial escalating doses of paclitaxcl were given in combination with a fixed carboplatin dose of 300 mgim’,

while both drugs were escalated in the ovarian cancer study. In both studies paclitaxcl was infused over 3 hours and carbaplatin over 30 minutes, and cycles wz repeated every 4 weeks. The most frequent side effect has been neutmpenia, although this did not result in any infectious cpisodcs. Alopecia and mild cmcsis also have bum frcqucntly mwuntcrcd. Mild skin reactions have been rcportcd in a few patients. Bone pain and myalgia occur more frequently at the highest paclitaxcl doses. No diffcrcnce in toxicity has been observed thus far between the hvo drug sequences in the NSCLC study. Both studies arc still accruing patients as the maximum t&r&d doses of paclitaxcl in combination with carboplatin have not yet bea reached (carboplatin 300 m&n’ with paclitaxcl 175 mdm* in the NSCLC study, carbaplatin 400 mg/m’ with paclitaxel 150 mp/m’ in the ovarian cancer study). An investigation of maximum tolerated doses with granulocytc colony- stimulating factor support is planned tbcreat?er.

Loag-tennsuhvalat3ercbemotberapyamtaihgplatinumderivtivw bt patients with advanced unresectable noo-small cell lung cancer Sculier J-P. Pnesmans M, Libcrt P, Bureau G, Dab&s G, Thiriaux Jet al. Service deMedecine. Inxtihtte JulesBordet, I Rue HegerBordet B-IOOOBnuelles. Eur J Cancer Part A Gcn Top 1994;30:1342-7.

The study set out to dctcrminc the rate of long-term survivors (LTS) in paticnts bated with platinum-containing chcmothcmpy for advanced non-smell cell lung cancer (NSCLC), to identify prognostic factors predicting longterm survival ( 2 years) and to report the LTS natural history Eligible patients with advanced NSCLC treatcd by chemotherapy in one of seven bials conducted by the Europca Lung Cancer Working Patty from December 1980 to August 1991 were included. All patients received cisplstin end/or carboplatin. Of these, I052 patients wcrc eligible and 24 variables wcrc analyscd as potential prognostic factors. Achwial2-yw and S-year survival rates were, respectively, 7.4 and 1 .S%. All paticnts surviving for %5 years had limited discax and were treated by complementary chest irradiation and/or surgery. Univariate prognostic factor analysis for LTS identified as significant no major weight loss, limited disease, no liver metsstases, normal white blood cells and ncutrophils and normal lactic dehydrogenasc Ievcls. By multivwiatc analysis, tbc only significant factor was limited disease. Objcctivc rcsponsc to chcmothcrapy was also found to be, as disease extent, .a highly significant predictor for LTS. Thus, the two best prognostic factors for LTS wcrc non-met&& disease and response to chemotherapy.

Alteration of coagulation and tibrinolysis systema after multidrug aoticttncer therapy for lung cancer Gabazza EC, Taguchi 0, Yamakami T, Machishi M. Ibata H, Suzuki S et al. Me Universi&WacolqWea%cine, SrdDqa qflnkmalMedicine, SlJEdobashi, 2 cho-me I 74 Bonchi, Tsu ci% Me. Eur J Cancer Pti A Gcn Top 199430: 1276 81.

Recently, an increased frequency of thrombocmbolic events has been rcportcd at&r tbc administration of anticancer drugs. The precise mechanism by which these vascular phenomena occur is unknown. The current work aims at evaluating the alterations of the coagulation and the tibrinolysis systems during the administration of antineoplastic agents by means of newly developed markers of hacmostasis. This investigation comprised 25 lung cancer patients treated with multidrug combination chemotherapy. D-dimcr, plasmin-6,- antiplasmin complex, fibrin degradation products, fibrinogen, antithmmbin III, thrombin-antithrombin III complex, prothrombin time and activated partial thromboplastin time wcrc measured from samples taken before and on days 2, 5, 7, 14 and 21 after the administration of antineoplastic drugs. A significant reduction in plasma concentration of fibrinolytic activity markers, DD and PAP, was observed on days 5 and 7, and on days 2,5,7 and 14, respectively, following the administration of chemotherapeutic drugs. Statistically significant shortening of PT and APTT on days 2, 5, 7 and 14, as well BS significant elevation of the thrombin generation marker TAT were observed on days S and 7 after chemotherapy. These results show that rclativcly higher levels of coagulation activation and a lower tibrinolflic activity occur during cytotoxic drug therapy wmparcd with basal values. Small variations of hacmostatic values and a short follow-up period may explain why no thrombotic events were observed during this study. Although further studies must be done to clarify these findings, the results ofthisinvcstigation suggest that an imbalance ofthc coagulation-iibrinolysis system might be a contributing factor in the pathogcncsis of thrombotic complications during chcmothcrapy.