a phase ii trial of combination chemotherapy with cisplatin and etoposide in small cell lung cancer
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Abstracts /Lung Cancer 13 (1995) 81-104
tn six of ,he first 25 patients, subsqwnt doses were reduced by 40 mg (one capsule) in all patients. Rest&s: One hundred sixty- two palients were treated 138 with measurable and 24 with assessable disease One hundred two ~a(le”ts were men and 60 women. The mean we was 62 years (range. j6to83,. Tkoverall responw ratewas 14.5%f&at1e”ts wth measurable disease (95% mntidence interval. 9 3% to 21.7%). The median time u) ,rea,m&, failure (IIF) for all pahems war 9 week; The median survival time was 29 weeks; the I-year swvwal rate was 22%. Toxicities included grade 3 or 4 neulrqenia in 40%, which was depcndcnt on the vmorelbine dose. Cnher ,oxiei,~es included mdd 10 moderate naWomiling. diarrhea, and stomatilis. The mean dose m,ew,ty of vinanlbine was 53 mgim’. Conclusron: Oral vinorelbme admininered once weekly an active age”, in stage IV NSCLC Tbe mediansuwival,imcof29weeksis similar,ocha,ach,evedwi,h single- agent intravenous vinorelbine and more aggressive cisplalin-based combinations. Fwther studiaofthwcompound in Ihe palliawe-,n,en, care sntng appear to be indicated.
Early versus late alternating chemotherapy in small-cell lung cmeer Joss RA, Bacchi M. Humy C. Bernhard 1. Ccrny T . Manmclh G c, al Dwaon o, Oncolo~v, “epamnenl o/ h/ed,c,nc, ,V~nrnn~.,p,m,. (‘II- 6OOOLurern 16 Ann Oncol 1995.6.157-66
BockzmunrC From 1984 10 1989. the Swiss Grow for Chmcal Cancer l&arch (SAKK) perfomxd a randomwzd pha& Ill ma1 com- paring early verms late aRemating chemolhcrapy in palwu w,,h small- cell lung cancer. Pot,enbncd,~tetho& 406 ebeible palleMs werccn,cred m,o thetrial. Regimen A mns~stcd of PAV (&PI&. Adnamycm. VP 16-213. and Reeimen B ofCvMOC (Cvclwbos~ham,de. Mcthotrcwe. Oncovm. CCti) Cycles w&c repeated a; rap,dly as posstble Pa,~cn,s were randomized 10 reccwe alher ABABAB (early allcmaung chemolherapy) or AAABBB (late altcrnaling chemolhcrap)) ARcr III cycles patients w,,h lim,,cd disease m complclc or pamal rcm,ss,on and ,hose wlh ex,ens,ve disear I” complclc rem,sston rcccwcd irradiation 10 ,he primary (45 Gy) and ,he CNS (36 Gy). Xsrulfs The overall remission ralc was 87%. w,,h 31% complele rcmissmns The medm suwival of all 406 cbg,hle palicnls was 346 da?s. wtth 15% ol the patients alive a, Iwo years The overall renwsslon raw ,hc rale of complete remiwon. the medtan surwal and Ihc rale of long-,cml survival were not signdicantly d,lTcren, tn the two ,rca,mcn, arms In hm#,ed dwase the eslimalcd percenlages of survival a, 2 years uerc 33% m ,he early and 24% ,n ,he lale altcmalmg chcmothcrap) arms Palicms wth extensive disease survwed wgnificamly longer wilh la,c al,erna,mg chemaherapy dun on Ihe early allema,,~~ rcgmlen (mcdmn sunwal 336 days versus 301 days, p = 0 01) In the latlcr pa,uen,s ,he received dose intensmcs (RDI) ofasplalin. adriamycm and etoposlde were s,gniBcan,ly higher m the late-al,emaUon arm. Patients trcalcd with early al,ema,ing chemotherapy rated ,hcir tuner symp,oms. functional stales, fa,,guc!mala,se and rcstricwn of scaal acwi,y s,gn,ficantly belter. reflectmg an nmprwed subjective adJus,men,. Conclusions: Al,erna,,ra chemolhcrapy w,,h PAV-CV-MOC PIUS cons&dating r&nherapy~s a feasible andelfcnive vca,r&n, for s&II- cell lung cancer. with acceptable to&q. Whereas patients w,h early alternaltng chemotherapy achxve a belter subJecdve adjustment, late al,ema,,ng chemotherapy allows for a higher RDI 01 c,.splatm. adria- mycm and e,opos,de. which resulls m a signi&xUly longer muhan sunwal of paliems w,h extensive dtsease
Effects of swamin on human lung cancer cell lines Rubio GJ. Pine& HU. Wrizueln I, Van Ark-Otre 1. Giaccone G. Deprmrnt o~Onco/ogy. Fmc Unrversq Hosprrol, Amswdam. Eur J Cattar Par, A GenTop 1995;31:244-51.
Swamin cytomxic& was studied in a panel of human lung cancer cell lines bv the MTf assav The concen,ra,mns of swamin wh,ch induad 5&growih inhibition (IQ ranged from 130 10 3715 iM for theaelllinesgmwinginmediumconlaining IO%fe(alcalfserum l.FCS) In only one cell line was the IC.. at a concenlralion lbal can be reached in p&ma of palienu ,rea,ed $,h swamin. Summin was is and 3 3 times more cymtoxic on NCI-N417 cells growing in 2% FCS and in HITES serum-free medium.respectively. lhan growing in 10% FCS No difference in suramin cywtox,city was observed between small and non-small all lung cancer cell lines. Al ,k lower concen,ra,ionr teaed, suramin stimulated proliferation of ,he two small cell lung cancer cell her, NCI-HI87 and NC&N4 17. Of several growth factors Bsted, none Induced s,,mula,ion of grouZh ,n NCI-HI87 and NCI-N417 cell hnes.
“01 did lhey ,n any Way aller Ihe sll~ulal~ry e&l of ~U~XIII~. Cell coun,mg.lDNA flow cytometric analysis and K167 stammg confirmed a h,gher prohferawe swe m suraminexpoved NCI-HIP7 c,clls as compared ,,n,h un,rea,ed cells Howcvcr. topcnsomerase II-G gene expressmn remained unchanged. as assessed by nonhern blo, analysts and immunonammg Suramm had an mhihitory cUea on ,opmsomerax II adwily. as assnsed by ,he kDNA dcacnalion assay, wilh an IC,, of approuma,cly JO iM. In conclusion, suramin has signdican, cymtoxic a~trwty rn a mmonty of human lung cancer cell Imes, and I, stimulales prohlera,mn tn sane mslances The plemtropic action of suramm observed should cawon on the poss,b,li,y of lumwr acceleratmn !n pa,,en,s bemg tread w,h ,h,s drug.
The feasibility of using glycosylated recombinant human rrmukrcvtt cdostvstimubtinr factor fGCSFI to incrust tbe &ntd &e iota& of doxkubicitt; cyelophorphamide and
ttopddt (ACE) in the treammt of small cdl lung cancer Thaicher N, Andcrnon Il. Bbchea NM Girlii DJ, Lallemand G, hlachia D e4 aJ. h4RC Cancer Trials 0~JIce. ~ShaJ?esbuy Road, Camhridnc. Eur JCanxr ht A GenTon 1995~31:1526.
hrtber 5 had A& b&ted, 3 for to&ity and 2 for-progressive disease Of the 71 intewals betwam cycles, 42 (5%) were of the prescribed I4 day& 9 (13%) of 15-20 day& IS (21%) of21 days and fivc(~)bnga,butdurirythcfirslfau~l~36(7~)d47intmals were of 14 days. The main maso” fa sway was haunatological toxicity. All20~e(icntsexpcricnmlWm)~3or4oeuvopcnia,~at2 wrelLFnftcraeyclconly3hsdgadc4andlgde3.17pstientsroquired
mdv=crsc tcactbr~ to G&F was an episode of rash &h fxial &&ma.
tk interval between cycles.
Effect of proton pump inhibitor on cell growth and sensitivity to cir-di~minedichloropl~tinum (II) in non-small cell lung cmetr cell lines Bando T . Kasaham K. Shibara K, Nakatsumi Y. Fujimura M, Matsuda T . Thin, Depm,,en, ,n,en,o, Medicmc. Kannr& Univers,,j School Medtcme, 13-I Takammach,, Kana.nwa 920. Anticaancer Res 1994: 14-2727-30
Recently, the ,mporCance of Ihe potassium pump in the cellular a acculation of cisdiamminedichloropla,inum (II) (CDDP) has been reported. In this study we evahta,ed ihe mle of the proton pump as a detem,hwd of t.he sensitivitv to CDDP in non-small all hnp. cancer cell lines in vitro by using a &edve proron pump inhibitor, A&2000 PC-9 and PC-9/CDDP all lines, which are sensilive or resistant to CDDP. were used for lhese experiments PC-9ICDDP was 17.4-fold more resistant to CDDP lhan PC-9 cells. Relative resisumce was no( allered by coineubation with a non-cywoxic dodge of AG-2000. From these s,u&es, i, was shown that Ihc proton pump inhibitor AG-2000 did no, enhanae the sensitivity ,o CDDP However, as AG-2000 is no, cytotoxic and does rtc4 compromise ule CDDP-se&iv&y m NSCLC cells a, the mmentralion of clinical use for gastroduodenal ulcer. AG- 2000 can be used with CDDP ,n chemcaherapy for lung cancer
A phase II trial of combination chemotherapy with cisplatin
and etoposide in small cell lung cancer Ckon EM. Kim HG. Son T Y , Yuh YJ. Lee SG, Lee CT et al fiptirnen, oflntemal Medicine. KOWJ Cancer Cenler Hospital. Seoul. Tuberc Respir Dis l994;41:632-43
Backgmund: The objective responses of cisplatin and e,opos,de (PVP) mmbination chemotheraw as second-line theraw follotinp. CAV was high (40 -SO%) aed, in se& repon~, PW yield wvival &IS that are al least as gwd as those obtained wi,h cyclophosphamide or doxoruhicin-based regimens and wth less host-related toxicity in chemodwapy-naive patiews We conducted a phase II study ,o evaluae the effect of a combination of cispladn and eloposide as a tim-line
Abstracts/Lung Cancer 13 (1995) 81-104
lherapy in patienls wth small cell lang cancer. Methods S~xty-one previously untreated small cell lung cancer patents wth measurable lesion (s) received cisplalm (30 mum’ IV. day I - 3) and etoposlde( IO0 mp/m’ IV. day I - 3). In patnerds with limited disease, afler completion of 6 cycles of PVT’ chemotherapy, chest and prophylatic brain madiation was performed in case of complete responder, chesl irradmtnon only in partial responder. Resulrs. (I) Of 55 evaluable patients. I3 (24%) bad a compleb response and 29 (53%) had a pamal resp0n.w (2) The median suwival time was 55 8 weeks for all pattiems (N = 55). 6 I. I weeks for limited disease (N = 3 I). 5 I 3 weeks for extensive disease R‘I = 24). (3) The reswnse duration was 29. I weeks for responders ( N = 42). (4) There were m significant prognostic factors influencing response rates. (5) The toxicity was tolerable and there was no treatment-related deaths. Conclusron: The PVP mmbmation chemo- therapy as a first-bne therapy was effecrwe and a well-,olera,ed m patients wth small cell lung cancer.
Sequential functional imaging with technetium-99m hex&s-Z- methoryisobutylisonitrile and iridium-Ill octreotide: Cm we predict the response to chemotherapy in small cell lung cancer? Moren~ JL. Caglar M. Bcwia C. Cnllat-Wgoemn N. Morere JP Hopml Rv,cenne CHllBobrgny. Univewle Pa,,s.Y,,,, 125 Route de.%l,ngrczd F-93009 Bobtgny Eur J Nucl Med 1995:22 177-80
A case of small cell Lund carcinoma (SCLC) demonslralmg uptie on functmnal iridium-I Ii octreotide scinttgraphy is presented, Technetum-99m hexak,s-2-melhoxv,sobutvl,san~tr,le <MIBI) scm,,graphy clearly dclineatcd an ah&cc of ~dmnuclidc u&ke at the ,umour site. Thas suggested the presence of multldrug resislance- mediated P glywpmtcin (Pgp) on tumcarcclls, whuh recngruzes cermm chemotherapeutic agents as well as MIBI as a substrate and avoids radlonuchde conccntrataon. Follou~ng three courses of chcmothcrapy, lhep.went failedloImpro\eandeventually*cd Thtscascdemonsva~es the nnponance of func,mnal rmages. ahlch have Ihepotencd ,o prattct the outcome in response ,o chemotherapy
Obesity and therapy-related toxicity in patients treated for small-cell lung cancer Ceorgladls MST Steinberg SM. Hankins LA, lhde DC. Johnson BE. .\ononol lnsr,rures of Heollh, E/de 8. Belhesdo. MD 208X9 J NatI Cancer Ins, 1995:87;3616
Backgmund obese individuals have altered pharmacokme,cs for many md&mons when compared ulul tie mxwbese For the oncologist treamg an obese cancer panen!. these changes m drug dlsposllion may paenually cause mcrcaxd therapy-related toxicity As a consequence. oncolog,s~s frequently treat obese patients wnh dose reductmns m an eflort to decrease chemotherapy toxwty However. little clinical data cwt ,o cilher s~ooort or relate lhis polw Purpose. The clm~cal course of a cohon of ~;,enrs ,rea,ed for ;mali<ell lung cancer (SCLC) was e\alua,cd to determme II Ihe obese patients had an increase in therapy- relalcd loxtc~ty hlerhods. The study sample mcluded 262 pabents wllh hlstologlcally coniirmed SCLC treated in clmical trials from I977 through 1993. Before 1986, pa,,ents with hm,tcd rlage SCLC were treated wdh a cyclophospbamtde-based regonen with (n = 47) orwnhout (n = 46) chest radtotherapy. Subsequent pa,,ents with limited stage dwasc (n = 54) recewed etoposide and wplalin plus ,wicedaily chest rad~olherapy Patients with exleosive stage SCLC were randomly treated with scandarddosc (n = 46) or hnghdose ctoposade plus cisplalm (n = 44). poorask patients wrth extensive stage discase (o = 25) were assrgnd lo nandard dose noposlde plus c~splatm For all patients, aclual body weigh, was used when determming lmtnl doses of chemotherapy The measure of relative wenghl was the body mass index (BMI), which was calcula,cxi from the pre-treatmcn, haght and wgh, &,a The BMI was evaluated both on a contmoum and wlh pa,,enls grouped m,o BMI levels (normal. o&c. and severely c&x) Tooxtc~ty paramc,ers were collected durmg mducrnon chcmolhcrapy and were compared with the BMI In add,,,on. thcovcrall sunival of,heen,lrccohorl wasevaluated. wth pallcots divtdcd into ddTcrent groups based on theur BMI level Resulrs We performed 170 comparisons between the BMI as a ~ontmuum or the BMI level and Ihc I5 ,owdy parameters There were nocons~aenta~~aoanrafs~gni~~acancc foundbetween incre+sing BMI
or BMI levels and increang toxicity from lherapy When survival was evaluated. no statistically sianificard differences were found between . - the survival of padents wthin the ditferent BMI levels. Conclusmns: In this groopof262 patients with SCLC, obesiry at the stanoftreatment was not associated with increased toxicity from trealment or a shortened
survival. No suppa-~ for empiric chemolherapy dose reductions basal on ideal body waghI was evident fmm this audy.
Cirplatinktoposide combined with interferon-gamma in non- small cell lung cancer Pirkcr R. Prior C. wes R. Kneussl M. Oroszy S. Krajnik G et al. Clinic/or Inl@mml Medicme 1. Wohrwgegvrrel 18-20. lo90 Menno Radio1 Onml l994:28:395- 7.
In order to assess the clinical eficaq of interferon-gamma (IFN- gamma) in non-small cell long cancer OJSCLC), IFN-gamma was added to three cycles of chemotherapy (cisplatio. etoposide) and applied as maintenance therapy in patients with advanced NSCLC. &far. 32 patients have been admitted to thw trial. Twenty-nine oatients were evaluahle with regard to response. Complcte~remis~ions. partial remissions and minor responses were observed m O%, 7% and 28% of the pabents. respectively. Stable disease was see,, m I (3%) paben, and progressive disease in I8 (62%) patients In the casz of progresswe disease. the tream~ent wasdismolinoed. The duration of medmn survival was 7 months and the I-year survival rate was 40%. Only few patients did wewe LFN-gamma maintenance therapy. Funher follow-up of the patients is required morderto determinetheinfluenceorthis combined !rea!me”! 0” long-teml suN1val.
Hoosier Oncology Group studies in extensive and recurrent small cell lung cancer Emhom LH. Lochrer PJ. Unwersrrv Ilo,vpprrol. 550 X Innwwv HIvd Indmnopohs, ,A’ J620.1.5265 Semi,, Oncal 1995.22 Suppl 2 28-3 I.
S~gndicant advances have been made ,n the Ircaunen, of small cell lunncanceriSCLC)dwin~,epastIwod~~cs Ma~randwlw~lablc m~&ement has been &hi&cd in pahenls wih llmllcd dlseasc However. progress III errlensivc SCLC has been more clusw Dcspttc thousands of pa,,c”,s entered m,o numerous phase II and phase ill studies. d IS s,dl debamble whelher any pan~cular rcguncn 1s ropenor molder combination chemolhcrapy rcgmwis first sludxd 2O~cars ago From May 1989 through January 1991. 171 paucn,s u,lh c\,enrnc SCLC were entered inlo a Hoosier Oncology Croup phase Ill s(ud! companngeloposlde/clsplalin(W) wlh ctoposidc/lfoslanlldc/clsplaun (VIP) There were 166 patxnts fully walublc for rcsponsc and suw~\.aI As expected. hematologic toxnty was more sevcrc 11, Ihe pa,nUs m the VIP arm, bu, both arms had a 6% 10 7% treatnem-rclalcd monabl! rate The response rates were similar (70% v 66%. wtlh 18% and 2 I% complele remissions). However, there was improvcxi survval m ,hc VIP arm (P = .03). Th,s was rnos, pronounced at Ihe lad of Ihc sun.~\al curves. with 2- and 3. year s~rvwal ralcs of 12% and 5% for VIP .xmpared wdhS%andU?&for VP Adiffcrcnc formof VIPchcmothrrap! for paems with refractory SCLC wlh no prior llosfamldc also uas evaloated. From February 1990 10 August 1993. 16 pa,,cn,s \\lth previously treated SCLC were trcaicd wllh dad) oral etoposadci ifosfam~delasplattn Thlrty-onc of 4 I cvaluablc pa,~cnls had prior asplatin plus intravcnou cloposidc Myclosupprcsston was s~gnlficanl. with stx treatmen,-related deaths Twenty-lwo of4 I paUcn,s (54%) had an ob~eclwe response. mcludmg SIX (15%) complelc rcnoss~ons The mr,d~an length ofsurv~val was 29 weeks (range. I 10 76 weeks) Dcspllc the toxicily these rcsul,s arc compelitwc wllh man? firs,-line chemotherapy programs This IS a reasonable. aggresswe rcg,mcn for sclccled paucn,s wlh refractory SCLC
The place of ifosfamide in chemotherapy of small cell lung cancer: The Eastern Cooperative Oncology Group experience
and II selected literature update Enmeer DS. Johns Hodms Oncolow Cenler: 600 N iWle Y Ballr~norr, ,ULI il2.97. Semin O&l 1995:22&ppl 2 23-7 .
In a randomtzed Eastern CcqxrabveOncology Group study. smgle- agent ifosfamlde used 10 treat exteosivedtsease small cell lung cancer patients produced a 49% response rare compared with 56% for patients waving standard combmation chemotherapy (cyclophosphamldel doxombicir&mcristiine) When thedrug was combined ~8th carboplatin and etoposlde 10 Lreat extensive- daase small cell lung cancer patients, overall response rate was 83%. median suvival lime was 9 months. and I-year survival rate was 14% The major toxicity wets myelo- suppression. llwse resells confirm those oforher invest@ors who have shown the e,Rctivencss oftbe ifosfamide/cartaplab~elopoade regimen in treatlog patients with small cell lung cancer.