336 Abstracts/Lung Cancer II (1994) 323-344

neoplastic cells. In order to determine the relative contribution of the glutathione-linked enzymes towards mediating inherent cisplatin resistance in cancer cells, we have measured the chemosensitivity to cisplatin. glutathione levels and activities of glutathione S-transfe-, glutathione peroxidase, glutathione reductase and glucose&phosphate dehydrogenase in 8 cultured human small cell lung cancer (SCLC) cell lines with widely differing cisplatin sensitivities. Of these parameters, onlyglutathioneS-transferaseactivitycorrelatedwithdeg~ofcisplatin resistance in a linear fashion.

Sequencing and schedule efkts of cisplatin plus etoposide in small-cell lung cancer: Results of a North Central Cancer Treatment Group randombed clinical trial Maksymiuk AW, Jett JR, Earle JD, Su JQ. Diegert PA, Mailliard JA et al. NCCTGOO, 2OOFirsr Sr SW, Rocbes~er, MN555wS. J Clin Gncol 1994;l2:70-6.

Purpose: The combination of etoposide (E) and cisplatin (P) is an accepted standard therapy for small-cell lung cancer (SCLC); however, the optimal sequencing and administration schedule has not been defined. This study was designed IO evaluate different sequencing and administration schedules of E and P in the treatment of SCLC. P&cots nerd Merhodx Five hundred fifty-two eligible patients with limit& (LD) and extensive-stage (ED) SCLC were randomized to receive one of the following regimens: arm A, P 30 my/m by intravenous (IV) bolus followed by E 130 mgld boltts; arm B, E 130 mg/m’bolus followed by P 30 mglm’bolus; arm C, E I30 mglm’by 24- hour infusion and P 30 mglm’ bolus at the end of each 24-hour infusion of E; arm D, E 130 mglm’ by 24-hour infusion and P 45 mglm’ by 24- hour infusion on day 2 and 3 only. Two 3day induction cycles of IV EP were administered 4 weeks apart. Subsequent therapy was the same for all arms, consisting of four cycles of cyclophosphamide, doxorubicin. and vincristine (CAV) at (-week intervals. Consolidative thoracic radiation therapy (TRT)and prophylactic cranial irradiation (PCI) were administerul to responders. Resulrs: The overall response rate (84%) was similar in all treatment arms. Trezument arm A was associated with the best complete response (CR) rate (52%), the most favorable median survival time (MST) of 15 months, and a 26% 2-yeer survival rate. Patients with LD on arm A had a MST of 20 months and a 42% 2-Y-r mivd rate. Multivariate analysis indicated that extent of di-. pe&rmsnce~tatus,armoftherapy.and.sexweresignifi~tinde~ndent frtors influencing survival. Toxicity ofthe four regimenswas similar. excepl for greater thmmbocytopenia on arm D. Co&~ion: The bolus administration of EP with E following P for the first two cycles of cltmnotherapy was the most effective regimen, with especially esmntmging survival for LD patients.

Received dose-intensity: A randomized trial of weekly chemotherapy with and without granulocytecolonystimulating factor in small-cell lung cancer Miles DW, Fogarty 0, Ash CM, Rudd RM, Trask CWL, Spiro SG et al. Medical Oncology Clinic. Guys’ Hospital. St 7?mmas’St, London SE1 9RT. J Clin Gncol 1994;12:77-82.

P~rposc: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with smallcell lung cancer (SCLC). Pafients and Merho&: Forty patients with SCLC with good prognostic features (all patients with limited disease [LDl, and extensivedisease. [ED] patients with Eastern Cooperative Oncology Group (ECGG] 0 or I and plasma alkaline phosphatasc: levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with orwithout G-CSF. G-

CSF (S gkg) was self- administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin SO mglmr intravenously (IV) on day 1 and eto+de 75 mglm’ IV on dpp 1 d 2 alternating weekly with ifosfamide 2 g/m’ IV (with tnesna) and doxorubicin 25 mglm’ on day I, for a total of 12 courses. Dose ~ificotions(dosersductionsMdtreotmentdelnys)weremsdeaccordiag to defined hematologic criteria. Results: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in I1 of 23 patients in the G-CSF arm (P = .20). The proportion of ~ti~~experiencingdosereductionsduetoleukopeniawassigniticantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of23, P < ~34). Cycle delays due to leukopenia were similar in botharmsofthestudy. The RDI was 82% ofpmjected in thecontml arm (95% confidence interval [Cl], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). ~flcJ~&on: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of GSSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF PAL

Phase I/II and pharmacologic study of long-term continuous infusion etoposide combined with clsplatin in patients with advanced non-small-cell lung cancer KunitohH. WatanabeK. DepartmemofRe+atoryMcdicinc, Yokohama Municipal Citizen’s Hosp., 56 Okazawa-rho, Hodogaya-ku, Yokohama City. Kanagawa 240. J Clin Gncol 1994;12:83-9.

Purpose: The primary objective of this study was to determine thepharmDcodyMmicsofprdongedPdministrationofLow~etoposide by continuous infusion (Cl). We investigated the hypothesis that maintenanceofanetoposideconcentrationof 1 g/mLwouldbecytotoxic in non-smsll~ll lung cancer (NSCLC). Patients and hfefhods: Thirty patients with advanced NSCLC without prior chemotherapy or radiotherapy were treated with etoposide at 20, 25, or 30 mglm’ld infused continuously for 14 days (336 hours), following a IO-mglmr bolus. They also received cisplatin 30 mglm’ on chemotherapy days I, 2. and 3. Plasms concentrations of etoposide were measured by high- performance liquid chromatography at 0. 2, 4.24, 48. 120, 336, and 342 hours alter initiation of CI etoposide. Results: The maximum- tolerated dose (MID) ofetoposide was2.5 mglm’ld with leukocytopenia as the dose-limiting toxicity, Plasma concentrations of etoposide at steady-state(Css)showedapproximatelyhvofold interpatient variability at each dose level, and were greeter than I g/mL in most patients at higher dose levels. The severity of neutropenia was dependent on performance status (PS), age, and the Css of etoposide. The overall response mte for the 29 assessable cases was 28 96. Five of I 1 patients withaCs.sgresterthan 1.2g/mLmspondedtothethempy, whereasonly one of IO patients with a Css less than 1 g/mL responded. Conclusion: With long-term Cl of etoposide, 8 CSS greeter than l or 1.2 g/ntL appeared nsessnry, but not sufficient, to achieve a major response against NSCLC.

Phase I study of irinotecan and cisplatin with granulocyte colony- stimulating factor support for advanced non-small- cell lung cancer Mati N. Fukuolrn M. Kudoh S. Kusunoki Y. Matsui K. Nakagawa K et al. Deparrmetu of Intemal Medicine. Osaka Prefeenural Habikino Hacpital,&7-1 Habikino. HabikinoOsokaS83. JClinChtcoll994;12:~- 6.

Purpose: ~inceleukopeniawasoneofthedose-limiting toxicities of the combination of irinotecan (CPT-I I) and cisplatin in a previous

Abstructs / Lung Cancer I I (1994) 323-344 337

hial. we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-I 1 doa in combination with a fixed cisplatin dose. Prrrienrs nruf Mel/r&: Twenty previously untreated patients with stage IllB or IV non-small&l lung cancer (NSCLC) were treated with CPT-I 1 on days 1,8. and 15 in combination wirh cisplatin 80 mglm’ intravenously on day 1. In addition, rhG-CSF (2 g/kg/d) was administered on days 4 to 2 1, except on the days of CPT- I I treatment. The starting dose of CPT-I I was 70 mg/&. and the CPT- I1 dose was escalated in IO-mglm’ increments until the maximum- rolerated dose was reached. Results: Diarrhea was the dose-limiting toxicity aI 90 mg/&. Two of six patirnts experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CFT-I I dose from 80 to 90 mglm’ resulted in a marked increase in the plasma concentration of 7-ethyl- IO- hydmxycamptothecin (SN-38). Occurrence of diarrhea was well cor- relatedwith thepeakplasmaconcentration(Cmax)ofSN-38(P = .035). There were 10 partial response.5 (50%) among 20 paIients. Conclusion: The recommended dose for phase II studies is 80 mglm* ofCPT-I 1, and 80mg/m’ofcisplatinplusrhG-CSF. Wirh theuseofrhC-CSF, theCPT- I I dose can be increased 33 % above that in the original regimen (60 mgi m* of CPT-I I and 80 mglm of cisplatin).

lmmunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer Zangemeister-Wittke U. Collinson AR, Frosch B, Waibe.1 R. Schenker T, Stahel RA. Division of Oncology, University Hospital. 8044Zurich. Br J Cancer 1994;69:32-9.

The present study describes a comparison of two potent immunoloxins which utilise an identical targeting component, a monoclonalantibody(SEN7)speciticforsmallcell lungcancer(SCLC). conjugated to two different effector components. blocked ricin (bR) and Pseudomonas exotoxin A (PE). SEN7 recognises a novel epitope on the neural cell adhesion molecule (NCAM) which is highlymiatd with SCLC. The immunotoxinsSEN7-PEandSEN7-bRwereselectivelyand pofenrly active against a number of SCLC cell lines. of both classic and variant morphologies, inhibiting Ihe incorporation of PHjleucine with IC, values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial ratesofproteinsynthesisinhlbitionoccurred with &valuesof6.5 h for SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced Ihecy~otoxicactivityofthewr?aklyactiveSEN7-ricinA-chain by2, IOO- fold and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logsofclonogenic SW2 tumour cells were selectively eliminated from Ihe cultures during continuous exposure to the immunoloxms SEN7-PE and SEN7-bR respectlvzly. while antigen-negative cells required up 10 l,CCO-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR trealmenl in Ihe cultures did not express NCAM and consequently were noI selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE show& no alteration in NCAM expression bur were more resistant to intoxicalion mediated by PE. Tht~ cells were still sensitive to SEN7-bR.

Constitutive production of multiple colony-stimulting factors in pafients with lung cancer associated with neutrophilia Adachi N, Yamaguchi K, Morikawa T. Suzuki M, Matauda I, Abe K. Growth Factor Division, Nat1 Cancer Center Research Inst. Tsukiji S- I-I, Chuo-ku. Tokyo 104. Br J Cancer 1994;69: 125-9.

Pmduclion of colony-stimulating factor (CSF) was examined in Ihree patients with lung cancer associated with neutrophilia. All three patients presented a marked increa.. m neutroptnl count (26,000- 39,COO I ‘) that continued al least for 3 weeks and rapidly disappearti after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissw stimulated the colony formation of bone marrow myeloid progemtor cells in vitro. Northern blot analysis of poly(A)’ RNA from the tumour tissues revealedaconstitutiveexpreseion of granulocyte (G). macrophage (M), and granulocyte-macrophage (GM) CSF genes in all turnours. Immunoassay specific for these CSFs revealed that G-and M-CSF immunoreactivily was detected in all CM and GM-CSF pro&n in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or ncnr-normal range afier operalion. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither sllmularrd haematopoictic colony formarion nor contamed immunoreactivr CSFs. These results indicated that the neutrophdia found in the three patients was prohahly caused hy con&u& producrmn of multiple CSFs by lung cancer crlls.

Inhibitory effects ofcholera toxin on in vitro growth of human lung cancer cell lines Kiura K, Watarai S, ShibPyama T. Ohnoshi T, Kimura 1. Yasuda T. /n.rr Cellular and Molecular Biology, Okayutna lJniwr.sity Medical School, 2-S-I Shikotu-rho. Okuyuma 700. Anti-Cancer Drug Res 1993;8:417- 28.

Cholera toxm (CT) inhibited the growth of three out of IO small cell lung cancer (SCLC) cell lines and two out of seven non-small cell lung cancer (NSCLC) cell lines when tested by 3-[4,5dimethylthiazol- 2-ylj-2,Sdiphenyltetrliumbmmide(MTT)assay. TheseCT-sensitive as well as CT-resistant cell lines bound well to the non-toxic CT-B subunit-fluoresceinisothiocyanateconjugate(FITC-CTB)whenassayed by llow cytometry. Using the reaction of horseradish peroxidasr- conjupatal CT-B (HRP-CTB) on thin-layer chromatography (TLC), we analyzed gangliosides extracted from SCLC cell hnes. CT-resistanl SBC-I, minimally CT-sensitive SBC-3 and CT-sensitive SBC-5. HRP- CTB was found 10 react not only with GM I, hur also wlrh Fuc-GM 1, GDlb and other gangliosidrs on TLC. Although CT-rrslslanl SBC-I cells bound well to FITC-CTB. the binding of gagliosidcs rxlracted from SBC- I cells to HRP-CTB was markedly decrea.4 when compared 10 those from CT-sensitive SBCJ cells. The CT resistance of the minimally CT-sensitive SBC-3 cell lines, which binds wakly FITC- CTB and HRP-CTB. was partially reversed by exogenous G.Ml pre~reatmmt. ~aob.~rvationssuggestthattheamountofgangIiosid~s, such aa GM 1, FucCM I and GDI b. on the cells, rather than the CT- hinding abilily 10 the calls. plays a major role in cytoloxiclly by CT.

Urinary-derived monocyte-colony stimulating factor (P-100) following treatment with carboplatin and etoposide in small cell lung cancer (SCLC) Van HoefMEHM, Redford JA. Jones A, Smith IE, Earl HM. Wall PJ 21 al. Ann Oncol 1993;4: 877-81.

Backgroundz The hrmatopoietic growth factor P-100 is a monocytesolony stimulating factor purified from human unne and has been reported to reduce nwtmpenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patienls receivingintensivecbemothempy forSCLC. Yudyderign:Chrmorherapy consisted offour 28 daycyclesofcarboplatin (C)600 mg1m’i.v. onday I ofcycle 1 + 2and3OOmgl&i.v. onday I ofcycle + 4andetoposide (E) 120 mglm’ i.v. on day I-3 ofeach cycle. Pa&znts were random&d 10 receive P-100 for ten days following chemotherapy during either rhr