4-Ipomeanol: A novel investigational new drug for lung cancer Christian MC, Wittes RE, Leyland-Jones B ct al. InvesfigarionalDrug Branch, Cancer Therapy Evaluation Program. National Cancer Insti- tute, Nationallnstitutes ofllealth, Bethesda, MD 20892. J Nat1 Cancer Inst 1989;81:1133-43.

4-Ipomcanol (IPO) is the firsr agcm 10 undergo preclinical devclop- ment ar the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agem targeted against lung cancer. This disease- specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, prefcrcntially withm the mammalian lung, specifically within bronchialar Clara cells, and ihat its predominant toxicity was to Ihc lung m most species. IPO is inaclivc or only minimally active against most conventional antitumor test systems. However, some human lung cancer ccl1 lines, as well as a variety of fresh human lung tumor biopsy spccimcns, have been shown to bc capable of mediating the in situ biotransformation of IPO to a po~cmially cytotoxic imcrmcdlate. In this report, the biochemistry, metabolism, prcclinical pharmacology, and toxicology of IPO are rcvicwed and Ihe clinical development plans for this unique and challengmg new agent arc prcsenlcd.

Phase II study of iproplatin (CHIP) in previously treated small-cell lung cancer Granfortuna JM, Newman N, Ginsberg SJ et al. SUNY-Health Science Center, Syractue, NY. Am J Clin OncoI, Cancer CIin Trials 1989;12:355- 7.

Eighteen pa&m& with previously Lrcatcd cxtcnsive small-cell carci- noma of Ihe lung were cntcrcd into a Phase II study employing iproplatin (CHIP), a cis-platin analog. Patients had received a mean of two prior chemotherapeutic rcgimcns. Fifty-five percent had received prior c&platinum and 33% had received prior radiation therapy. CHIP (225 mg/m2) was administcrcd by intermittent intravenous infuslon over 30 min for 5 days of a 28.day cycle without prchydratlon. Sixlccn patieno: with Zubrod performance scores of 3 rcceivcd 27 courses of therapy (mean 1.7,rangc 1-6).Oncpartialrcsponscof 167daysduralion was obscrvcd, with complctc rcgrcsvion of involved lymph nodes and stabilization of noncvaluablc discasc in Ihc chcsl. Six patients had stablcdiscasc followingonccyclcofCHIP,butalI progressed following a second cycle of drug. The main toxicity was myelosuppression with prominent thrombocytopcnia. Median survival was 75 days from initia- tion of therapy. In this group of heavily pretreated patients with advanced disease, iproplatm has only minimal activity as a single agent and dots not show non-cross-rcsistancc with cis-platinum.

Chemotherapy ofadvanced non-small-cell lung cancer: A random- ized trial of three cis-platin-based chemotherapy regimens Hainsworlh JD, Johnson DH, Handc KR, Grcco FA. Division ofOncol- ogy, I’anderbdt Universuy School of Medicine. Vanderbilt Clinic. Nashvrlle, TN37232,Am JClinOncol,CancerClinTrials 1989;12:345- 9.

One hundred fifty-rwo patlcnts with locally advanced or mctastatic non-small-cell lung cancer were rdndoml/.ed LO rcccive lrcatment with one of three cis-plalin-containing chemotherapy regimens: vindcsincl cis-plahn, eloposide/cis-platm, or vindcsinc/ctoposide/cis-platin. Fol- lowmg an R-week induction course of trcatmcnt, patients wcrc evalu- ated forresponse: rcspondcrs continued LO rcccivc monthly chcmothcr- apy. All patients were followed until death. Rcsponsc ralcs for the ihrcc rcgimcns wcrc 10%. 6% and 24%. rcspcchvcly; the cis-platin/vindcs- incictoposidc regimen produced more responses than did eiticr cis- platin/etoposide or cis-plann/vindcsinc (p < 0.05). Howcvcr, median survival was not improved with !hc three-drug rcgnncn, and myelosup- prcssion produced by this regimen was worst. The 20.week median suvival for thcemirc group suggcsLs that these trcatmcnts had no impact on survival. None of lhesc regimens can bc rccommcndcd for routine

lrealmcnt of paticnrs with advanced non-small-cell lung cancer. The addition of vmdcsine did not make a significant impact in response rate or ovcrall survival in this study.

Alternatingchemotherapy Gthor without VP-16inextensive-stage small-cell lung cancer EvcrsonLK, JettJR,O’Fallon JRetal.(;argo ClinicCCOP,Fargo,ND. Am J Clin Oncol, Cancer Clin Trials 1989;12:339-44.

In this study, we evaluated the role of alternating chcmotbcrapy with or withoutctoposide (VP-16) in patients wilhcxtcnsivc-stage small-cell carcinoma (SCC) of the lung. All patients rccclvcd initial treatment with CMC ([cyclophosphamidc, mcthouexa@ and chloroethyl-cyclo- hcxyl-nitrosourea (CCNU)l. Four weeks after initial trcatmcnt. patients were stratified by pcrformancc score, central nervous system (CNS) mclasmsis, age, and response to initial CMC therapy and randomized to

receive A0 (doxorubicin and vincristinc) or AVO (doxorubicin, VP- 16, and vincristine) alternating with CMC. One hundred eighty-two eli- gible palicnls were trcdtcd with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to eitbcr AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly diffcrcnt on Ihe two trcatmcnt rcgimcns. Toxicity was significandy greater for patients rccciving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression or sur- vival of patients with extcnsivc small-ccl1 lung cancer.

Limited small cell lung cancer: possible prognostic impact of initial chemotherapy doses Aniagada R, De The H, Le Chevalier T et al. The Commirfee of Thoracic Diseases, Institut Gustave-Roussy, Villejuif: Bull Cancer 1989;76:605-15.

While the effect of chemotherapy dose on tumor response in small cell lung cancer has been fairly well established, the effect on survival has been retrospectively analyzed only in some series. This particular point was studied in a series of 52 consecutive patients with limited small cell lung cancer treated by an alternating radiotherapy-chemotherapy sched- ule. The induction trcatmcnt consisted of 6 chemotherapy cycles (the planned doses were: doxorubicin 40 mg/m2 day 1, VP16213 75 mg/m’ days 1-3, cyclophosphamide 300 mg/m*days 3-6, and cisplalinum 100 mg/m* day 2) alternated after the first 2 cycles with 3 courses of thoracic radiotherapy delivering a tolal dose of 55 Gy. Eighty-one percent of patients went into complete remission and the 3-year relapse-free survivalwas24%.Amultivariateanalysisofprognosticfactorst~kinto account age, sex, T stage, performance status, delayed hematological toxicity to lhe firstcourscofchemothcrapy,actualdosc/m2ofeachdrug during the fist course and mean dose/course delivered during the induction ueatmentaftcrthc firstcyclcofchcmothcrapy. It was possible to identify 3 independent factors influencing overall survival and relapse-free survival: actual initial dose of cisplatinum, actual initial dose of cyclophosphamide and [he T stage. The effect of the initial dose of cisplatinum and cyclophosphamide proved to be linear on relapse- freesurvival.Thercsultsofthisanalysisshow apossibleeffectoninitial doses of chemotherapy in the management of limited small cell lung cancer in terms of both distant metaslasis and overall survival rates.

Phase II study of N-methylformamide, spirogermanium, and 4- demethoxydaunorubicin in the treatment of non-small cell lung cancer (EST 3583): An Eastern Cooperative Oncology Group study Ettinger DS, Finkelstein DM, Donehower RC et al. Johns Hopkins Oncology Center, Baltimore. MD 21205. Med Pediatr 0x01 1989;17:197-201.

One hundred forty-four patients with non-small cell lung cancer, the majority (72%) of whom had received previous chemotherapy, were evaluable in this randomized phase II study of N-methylformamide (N-

MF), spirogermanium, and 4.demcthoxydaunorubicin. There were two partial responses, one each with spirogermanium and 4- demethoxydaunorubicm. There were tight life-threatening comlica- tions (mosdy hematologlc) and two l&al complications (N-h4F, hematologic; 4-demethoxydaunorubicin, gastrointestinal). The overall survival ranged from 9 days to 533 days with a median of 17.6 weeks. The following factors were associated with poor survival: Poor initial performance status, prior weight loss, presence of liver or subcutaneous metastascs.

Influence ofdocosahexaenoic acid on cisplatin resistance in a human small cell lung carcinoma cell line Timmer-Bosscha H, Hospcrs GAP, Meijcr C et al. Division Medical Oncology, Deparfmem oflnlernal Medicine, University Hospital, 9713 E% Grnningen. J Nat1 Cancer Inst 1989;81:1069-75.

In a scnsttlve, human cell lung carcinoma ccl] lme (GLC,) and a cisplatm (CP)-resistant sublme (GLC,-CP), the effect of co-culturing with docosahexaenoic acid (DCHA) on CP cytotoxicity was studied. Cells were cultured for 4 days, with 32 pM of DCHA added on days 1 and 3. Incorporation of DCHA into the cellular phospholipids was demonstrated by fatty acid analysis. Supplementation with DCHA led LO almost a threefold decrease of resistance in GLC,-CP and had no influence on CP cytotoxicity in GLC,. After culturing with DCHA. cellular platinum (Pt); total Pt bound to DNA; and PI-GG, Pt-AG, G-Pt- G. and R-GMP adduct comer&s mcreascd in both lines, whereas interstrand cross-link formation was elevated only in GLC,-CP. These cxpcrimen& demonstrate that DCHA reduces CP resistance. Although an effect on cellular membranes resulting in an increased CP uptake apparently was present, thin mechanism does not seem LO be responsible for resistance modulauon. Rather, an effect on nuclear, probably DNA- related, structures is likely and lcads 10 an increased formation of interstrand cross-links m GLC,-CP.

Primary chemotherapy ofbrain metastasisinsmall-celllungcancer LeeJS.Murphy WK,Glisson BS,DhingraHM,HoloyePY,HongWK. Division of Medicine, Department of Medical Oncology, University of Texas MD. Anderson Cant-er Center, Iious~on. TX 77030. J Clin Oncol 1989;7:916-22.

Founeen padents with brain mctastases from previously untreated small-cell lung cancer (SCLC) were treated with tiec courses of systemic chcmothcrpay ah an initial mode of treatment. Whole brain Irradiation was given concurrently with the fourth course of chemother- apy. The chemotherapy consisted of cyclophosphamide, 600 mg/m’ intravenously (IV) on day I; doxorubicin, 50 mg/m2 IV on day 1; vincnstinc, 1.5 mg IV days I and 5; and etoposide, 60 mg/m* IV days 3 through 5; all repeated erery 3 weeks with dosageadjustments. There were Len men and four women, with a median age of 59 years (range, 47 to 75). Six patients had multiple bram Icsions,and the bram was the sole silt of distant metastasis m four patients. Three patients were inevalu- able for response m the bram, as two died early and the third dropped out of the trial too soon. Brain lesions responded to chcmolherapy in nine (onecompleteremission [CR],cightpartial remwions (PRJof 11(82%) evaluable patients, and objective responses in the extracranial lesions were documented in nmc (one CR, eight PR) of 12 (75%) evaiuable pat&w. Median survival was 34 weeks(range, 1 to93). andtwopatients are still alive. Toxicity was sigmficant, with severe granulocytopenia (< SOO/pL) and thrombocytopcnia (< 5O,OOO/pL) observed in 85% and 15% ol patlcnts, rcspectlvcly. SIX patients had major mfcctiouscompli- cadons, wtuch resulted In septic deaths in two. However, there was no dc~cnoratmn of ncurologic stau~s durmg the Initial phase of treatment withchemotherapy. Weconcludcthatsys~em~cchemothcrapyalonccan mducc ObJcctivc regression of mcastatic brain lesions in patients with prevmusly untreated SCL.C.

Effect ofartificial electron acceptors on the cytotoxicity ofmitomy- tin C and doxorubicin in human lung tumor cells Kcizer HG, De Leeuw SJ, Van Rijn J, Pinedo HM. JocnJe H. In.\rirute of Ilumun Genelics. Free Universit). 1007 MC‘ Amwrdam. Eur J Cancer Clin Oncol 1989;25: I 113-R.

The cylotoxicities of miromycm C (MMC) and doxorublcin (IlOX) have been proposed LO depend on intracellular reduction by reduced flavoprotcins. WC mvestigatcd whether MMC- and DOX-Induced cyto- toxicity could be inhibited by competing for eleztrons lrom reduced flavoproteins by tie artificial electron acceptors phenazme methosul- fate(PMS),menadione(MEN)andmethyleneblue(MB). InintactSW- 1573 human lung tumor cells these compounds proved to be excellent electron acceptors, as judged from their capacity I:O Induce high levels of cyanide-resistant respiration. In addlnon, PMS, MEN and MB were found to decrease the cytotoxiclty of MMC, by 90, 63 and 29%, respectively, at concentrations thai wcrc thcmsclves completely non- loxic. In contrasi, DOXcytotoxiclty wa., nol deteci2lblr affected. These results suggest that in SW-1573 cells flavoprotcu-medla~cd bioreduc- tion isrcqu~rcdforthecytoiox~ccffectofMMC,but not for IhatofDOX.

Chemotherapy in non-small cell lung cancer (NSCL( ) Klaslersky J. Servicede Medecinelnreme. 1ns111ut.l. Bnrder. Cenrre de.7 Tumeurs, (Iniverslre Lihre, 1000 Brruulle.\. Eur J Cancer Clin Oncol 1989;25:1035-8.

Curing patients with NSCLC reprcscnts a fanlaslic challenge since the presently achievable results arc poor and the number of patients to be helped is large. Tbe role of combined modality approaches will cerlainly continue to be an active area of clinical research in the near future; the goal for these invesdgalions remains the drvelopment of an active chemotherapeutic regimen for NSCLC.

Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses Tashiro T, Inaba M, Kobayashi T et al. Cancer Chenzotherapy (‘enter, Japanese Foundation for Cancer Research, Toshrma-ku. Tokyo I70 Cancer Chemother Pharmacol 1989;24: 1X7-Y2.

The rcsponscs of I4 lines of human lung cancer senugrafts m BALB/ c-nu/nu mice to eight known antitumor agents were investigated. These xenografti consisted of four small-ccl1 carcinomas (SCLC) and ten non- small-cell carcinomas (four large cell, three squamous cell. and three adcnocarcinomas; NSCLC). The doses used m Ihe experiments were the maximum tolerated dose (MTD) in nude mlcc alnd the ‘rational dose’ (RD), the latter considcrcd to bc pharmacokinetically equlvalem to the clinical dose. When given at MTDs. all drugs cxccpt i-lluorouracil(5- FU)andmcthotrcxate(MTX) wcrccxucmclycff~~ct~vcaga~nst NSCLC as well as SCLC. The response rates of drug-scnsnive SCLC to milomycin C (MMC), ACNU, and vinblasunc (VLB were 100%. and those to Adriamycm (ADR) and vmcnstmc (VCR) were 75%. In addnion, the responseratesofeven drug-resistant NSCLC to MMCand VLB were 70% and 90%. respectively. In contrasll. the response rates of NSCLC 10 RDs of the drugs were reduced to <41X% and corresponded well LO Ihc rcspectlve clinical ralcs. In SCLC. :j good correladon of experimental and chnical rcsponsc rates was obscrvcd with four drugs lcyclophosphamide (CPM). ACNU. VLB, and 5-Fl:I. As a result, we cmphasi/*:thatamorcrcasonablcprcdlcilonofth~clir~~caleffcctlvencss of antitumor agcms can hc made by a protocol uL,ng ~~lm~ally cquiva- lent doses.

Combination chemotherapy with methotrexate, adriamycin, cyclo- phosphamide and CCNU (MAC0 for nonsmall cell lung cancer. 4 Year experience with 92 patient5 Bucchcri G. Fcnigno D. Vola F. Curc~o A .%letfl,,a/ Ocparmen~s.