Document 5Debmyr1qZzo26Vae5dKZoDz4

Cancer Clin Trulls 2. 291 -.J/0 l{)79 Nitrosoureas: A reapprai of clinical trials \jjri111 1'. K.il/ Mi) him ii t;luk m iih jin MTHOsmlUAS I RCM (.CM inethvICCM i :cpi,t'scnl a new < Uiss ul .ml iin-npl.isl u agi'iils will. .1 uriwil s|ieclrum "I antitumor activity l'ln-\ arc cell'cvclc nonspecific cvtotoxic agents Postulated modes of action and pharmacology of these nitrosoureas are reviewed Tln ir thera|)eiitu' effectiveness as single agents and in ,ii|iil>nialiiins have lieen recognized in malignant Ivmplmmas, multiple iiivclnin.i uii'Linotiia. ghohlastmua imiltiforine. gastric and mloreetal carcinoma, and aiiall-vrll earcnioiua ol the lung The nitrosoureas ate ,nliuinisleied on an internutlenl (i S-vvcck schedule |H., .uise nl ilelas eil and I mpiclitlv sesete I Mine mat mss i.Mills \\ hull m.is I s' 1111111 ll.it i s e in nailin' he intriisiiureas are a group of cell-cycle nftu; Tspeiihe .nitineiiplastii agents which have a"'"\, I ii i i.itl speitium III activity against a number nl animal tumor systems and against human hema tologic malignancies and solid tumors.1-2 They are svnergistic in combination chemotherapeutic regimens, have the ability to cross the blood-brain barrier w hen administered systemically. and may In- administered as single doses at approximately (i-vveek intervals. Two nitrosoureas, l,T-bis(2chlorocthvl)-1-nitrosourea (lU.'NU.Carmustinc1^) and 1 (2-chlorncthyl)-.'l-cyclohexyl-l-nitrosourea ((XIM , l.oinustine ''). have recently liecotne commercially available. A third nitrosourea. 1(2-ehlor<H'thyl)-'5-(4-methyleyclohexyl)- 1-nitrosMiiicii (inrthsl (.CM1, MeCdNU, Semiistine remains invesligalional We have reviewed (he published data on these three nitrosoureas to define and highlight their present and potential future roles in eoinlnnation chemotherapy anti to focus 111 ii m their spectrum of action anti unpredictable hemaloli'gie lovieils \ lourlh nitrosourea, slrepto/ntot iu. has recently lieen levievved m detail anti vv til not he discussed here. * 4 M, i | U 11 < >| m t il< >14V S< i I |i >11 ^ .lit I Ml \ i t Ml \ St III * 11 >1 Ml I In 11 It \l \S II t \ 4 M < I || it It l 1 n l|1 I |t'1M.ll('llli;v OmultlliS St i l H HI l IIIMIMls ol IVniiwI uiii.i St lttt| t if Mrdn iiii` I'ltil.itlfllilfht fVlili'A K .ini.t \ii,c i it ,tit ( .ittt cl SiH irt\ Jiiniitr l .n nit v ( limt .it I'cllim Prcelinicul studies lu IhV) (hccnc alitl (Ireenlverg noted (hat I11 let I is !-> -ml to-1 -niliosogiiainiline (\1\ \( I) vv as clli'i live ol piolonguig the life span ol mice rei civ mg milapt'iiloneal implaiit'ot 1.1210 leuke mia 1 Tins tliseoverv let) to a systemic search ol i ompoimds structurally related to \1\N(! It was ..lismvidlh.il I nielhvl I nil I osi nil-ea (SI M I vv .is mini' i I lit live than M\N(. in mi ! casing the liosl lih span ol nine ili|cctcd inira|>ei'iliuieallv ol siiIk iilaneously with 1J2H)1' M\L "as also elleclivi' against mtraeerehrally implantetl 1.1210 2!l7 29* Nitrosourea1. Is.it/ (.lick li-ukcima Sulvei|notil delilici ate ss ulhesis ol oilier I-melhs I-1-mtrosiiro.i deny.discs icsi-aleil dial I \ ln\ 1 i I ill i "! In 11 | ml i osoin ea i IK Nt l liail i in .ills e potential in (lie UDI1 | mouse implanted w ith us mans as 10' I. I 210 cells mllapei ilmu alls oi 11)' 1.1 210 eells mtraeeielualh 1 Tin1 nitiosomca. I -12-cli|on n-I lit 11 ! i s eluhes\i I-iiiliosuiuea (( X Nt ), pmdiicctl nmir lines Ilian 01 Al m die esjici imental liealmeiit ol imir w till 1. 1210 and w as act is e m die Walker carcino sarcoma 250 and nielainnna It 10 liitnni' systems 1 ('(INI . w lien used in emnliiualion w itli e\ tnsnie araliinoside, ss as curative in iniee receding intras(mums implants ot 10' l .1210 cells es en w lien the nntiation ol treatment was delayed until 24 lioiirs lielore tile median das ol dead; s I i 2-eliloi i lelhs I l-o-( I met Its le\elolies \ I)-1' ni trosourea (met Its I ( X A t ) w as superior lo lt( IN l and (XAl in (lie treatment ol mice implanted with Lew is Inns' carcinoma Asa surgical adjus ant. in cmnhination w ith eselophosphamide. ninths I (XAl lined a signil leant piopoitmn ol ltl)T| mice that rivetsed suIk iiIuihsmis implants ol I ,ess is Inns; tumor esen si lien they were treated at a lime si hen hmn inelastases had occurred. These Illinois w eie mil eurahle at that lime si it li a ns "I the stan dard alks luting agents, antunelaliolites. mica al kaloids, dacliuoinscm, eslosine araliinoside. oi hsdross urea 111 Mollis I ( X At also (xisscsscd sn|iei lor act is its against the lelalis els uures|>onsis e Hid malignant melanoma and ( oil hreasl eareiiioma 1 Meelumisiii of antitumor action The lilt I list III I e;n ( |-`ili I I ale I ell is i le liouspeell it1 agents 111 Hosvever. there is a somesshat greater degree of cell kill in the M phase and (h S phase houndars ot die cell c\ele \lks lation and i arhains lation hale lieen suggested as the |)otenlial modes ol at lion ol the uitiovnueas, hut the piecise met hanisui is inicleai 1111 IK At inhibits |)NA synthesisol I'.hrlii h ascites tumor eells ill vitro"' and 1,1210 leukemia in nin 1,l` l uder cs|)cnmcnlnl conditions, IHAL is al ile to inluhil the ineorporal ion ol 1 X M or mate into purines ol |)N A and UN \ hut giealei mluhiI lou ol uueleie acid than ol pi olein ss ulhesis oconis It has Ihs ii suggested that IK Nt mleileies ss itli tin r/e now ss ulhesis ol puiine riLmueleolides and w ith the conversion ol purine uueleotides lo DMA BCNU AND OTHER NITROSOUREAS O It CLCH,C1VNCNHR NO BCNU: R CH,CH,Cl CCNU: R * MtCCNU; R CH, I II.( Ill I. Slnieliiral hirtmilas Inr the lialit'eimtm) ^ .(lk\ I \ lutmsimiv.iN liases 1 In addition lo its (mslnlated role as an a|. ks laling ageril. IK At mterleres selectively with die ulili/atiou ol Instidme or its nielulmlitej a, demonstialed in rim in miceliearing Id2l0usci|rt tumor cells and in human leukemic eells 111 ||(;\p in tilin i an inhilnl tin111111111ii> trauslerase, py, eu/s me w Inch trun.slers the loruumino group from lorinuuinoglnlauiale to letrahydrololic and 1 This suggests that 1UAI mas interlere ss ith oiie-earhnn nietahohsin ( X A l lalieled ss ith 1 X ! in die eselohessl moiety hinds eslenst sels to-pi oleins m the 1.1210 ini my. in ru n. to suspensions ol 1, 1210 cells tn vitro, and lo nucleic acids and proteins in vitro. (XAT |a. Ivied w ith 1 X 1 tn the ethylene moiety binds tnhoth nucleic acids and proteins but w ith far less avidity than (!(At labeled in the eselohessl ntoiels These data suggest that (X At modifies nucleic acids I is alks lation and pmlenis bs eselohessl i aib.iiui lation 11 Pharmacology Ml lluee mliosoureas are lipid soluble with uietlis I ( X A l lias mg llie greatest lipid solubility anil !t( At die least ""t X AI and lucthy I ( X AL aie ass nimetrii molecules w hieli are more easily i adiolabeled tlian IK At and vseri1, ill part, <leseloped lo studs the pharmacologic disposition of the niliosomeas I )is|msiliou sliidies ss ith 1 X . lalu ksl nitrosoureas suggest that IK Al( X At and moth) I ( X INI1 are lapnlls jbsuthed limn the gastrointestinal tract with peak plasma lesels ol degradation products appearing I (i hours after' adiuiiustration il' The Location ot P.afliotaDe BCNU iguen p o 1 (given i J t CCNU ig'ven p o i I'C-CaiDonyl mo* '*C-CyctoHe*yt m '`"C-CWofoettiy1 n Methyl CCNU (given '`C-CyUoheityl n I i1C-Chioroethytr \ AS "'Ini v " -in ah I' with "`v US 'ISClte* '.\r Hi," I ' I rum 1 1 This ;> lxu l'">lclv ISC " -111(1 'I la'* I mill v iilils "ids Hclcuhc\\ I 'lilts \t Isill lle- 'II (ll IM'.IS -III' I-U I mis Lite ( \\( i a ( i i\11 ii 4 in \i s \\ niter, p)79 29!) mu lewis el lliese (lei;i,kl.ilKm pioilui Is aie ,-t|iimieil -mil 'lie inui.tii e\( lelum is modeiateli ,u i Table I l |!aillolabeled lil'Nl lias ,i hall-lile ul .'54 limns In'll ipi en i 'I alls and Is, limn s w lien -an en nit i a imiisK Slits In . 0', n| 11 a' i adu ilal ii`I limn [I \l is reeli\ i i ed in lhe hi me In Ills hunts mill dually im leeal eseielmn '1 ( (At is icadils NilU'd \s hell ipwn malls si ith |>cah plasma lewis ,.11'd heliieen I and 4 limns \n intact drim is peel able ill plasma al am I line lullini ma an mal mill ( ( Nl l riliais esii'ilimi ul radii'Libeled (Al laries lietueen 5hb and 77b of an nralls Jnunistered dns*- depending u|mhi the location ol ij, i.ahiiLiliel " Melln I ( ( \l inidenliH-s |a`mnpt ml ahsmplimi nitli im ml.nl dnm delei'l.iblr iliseiptelitlv in the plasm.i I'eak plasma lewis ,cin lietueen 5 and 0 hours Nppmsnnalels lit)1) r.idiolalx-led mellii I ( ( \t can Im- reemered In In- hi me by AS liiiim -- I'nill nmed plasma lei els ol i adInael n it s pi i >1 in ,ji lelleet a cntiihinnlinn <>l plasma piolein bmdiim ini active enteinhepntie rei ill illation ol the ilejljilalimi pioihiels The eiiln ol the niliosonrea Paiadallon prodni ts into the i eiebiospnial llmii 1 Si-' is pioinpt tn ilhin >11 <i(> nimnles). eloseli arallels cliaimcs m the conciiiicnt plasma lesels ,| ladioaeln ill and mm lie n lated to the lipid aluliihti ol the | i.netil niliiismneas \h*uiliiie lewis TABLE 1 Disposition Studies with 14C-labeled Nitrosoureas in Man .pcauon ot Radiolabei Time lu f'e.tk Plasma Level (hours 1 Plasma HalMile ihoursl .Sir1 'given p o i ,given i V i Jnu igiuen p o i !4r t'rtfhonvl mowMy 1 3 1 IJC-Cvciotie*vl moiety 3 MC-Chloroelhyl moiety ".'Ihst >'CNU ujtvcn p u l l4t'C. Johexvl moiely 4 3 l4C-ChlOroethyl moiety 6 34 67 iliibt ph.iyi ;27 IseconO phase) 5 (first phase) >27 (second phase) -4 ftirsl plhlitM 72 iseeond phase) 36 m I In ( SL o| ma n ai r I 7 it I' i i il the simnllaneons plasma I, wls IU \( ( ( \ ( and melln I ( ,( At ; * a 11 w it I ii - detei Ii d as | he inlaet patent com pm mils m I lie ( SL' -1 -- I lie p.n mil ml 11 in mi e.i' do not ap|Mar to I m t he ailue a lit i nei iplasl n acents t heinseli es because I lies i am ml be 11 rm ii i d limn plasma, urine nr eeiebiospnial Hind altei ad m i nisi ml inn -1 -- ,\ nnmliei ol dimradalimi prodnels haw been [X>5Inlati d as the potentially active com|x>muls 21 These have mi hided 2-i lilorix-ths I isoevunate and 2-chlmiN'lhi lainine lor IKAl' and cyclnhexvl isoei anatc and i wlnliexi lamme lor (X)NL' Tile hepatic miernsmnal drim-metalx>li/ing system is minlwd in inliosmnea degradation Druti toxicity and dosage schcdtdinu I'lie < In ilea I use ol ml rosmireas as single agents m in mitllidnm emnbiiialimi regimens has been based mi the intei mil lent siimle-dose schedule and t In-hio.iil spei It uni ol aiilitumm activity \s smt'le agents m patients ivitb gix>d I nine mal mu reserve and limited prior eheinotherapv and m ladiolheiapv. HC.Kt is administered in ti. nenmisli in a dose ol 220 225 mg/m2cvei y 0 S necks (m SO mi;, in- intravenously daily X:> every (> S necks), ( (At is gisen orally in a dose ol 1110 I id mu mJ eimi (i S necks, and inelhil t t \l is mien malli m a dose ul 200 22-5 mg, mewii 0 S necks,-1' The intermittent dosage si liedulc nas dewlo|ied Ix-caiise ol delayed marlon lovieiti \dioeales of IWAl' Iraetiouatimi aiune Im somewhat less gastrointestinal tovieitv Ou.ilil.itiicli it is i lit I ii-i ill In discern major toMeilv dil leimn es ammm these lluee niliosmireas. I)elaved and prolmind bone marrow toxicity is the most serious side elici t of the nitrosoureas The tipieal (late) nadir is seen in all patients, nsnallv in cut i mg I let u ecu n eeks 5 and 5 lot platelets and weeks t and 7 lor grainilnevles and lasting lietueen I and 2 u eeks This delav ed nadir is an advantage n hen i isnm the nit i osi mreas m com Inna I ion with othm .mi nis that Ivpiealli haw an earlier myelosnppiessne aetimi since the nadirs are not su[>ernuposed \iie.nli granulncitc and platelet nadir mal be seen in one Imlllli to one- thud ol the pa tients nitmimglO I I da v s al tei the administralimi ol the nitiosiuea and lasliim I 10 (lavs2, as dmimust rated in I' inure 2 The early nadir predicts a more severe late nadir Approximately 1-254 of :S00 Nitrosoureas hat/, (Huh Methyl CCNU Hematologic Tonclty Pattern * 5ti s nl aune iletlr |W nitclumi glare is not fen in preclit Two v ases t ve Urn rep a^ritt nilriisou 1 tiiie patient rt patient receiv ^presents a c g present Anlineopi Several corr lished concer talv nl BC\ tit.tilt ;. Ui'iit.ilnlimii 11 .\i l 11 \ | Ml tel M * it inetlu I ( C ,\t u (ill dtililtlr n.iilu el Iruluipeiitu - |t i,s iin|)ortant neeessariiv in the sul islitutit I net II llislv mil II Mini | l,|(l< Ills ill! I Ill'll III si IV| M 1st |l I III a III 111IM ml c,i will evpe I letii e III e-t III mil 'Him; peiiplii'ial paneltu|Venui ill association with llusliim; \ Ii it al pltlel nils vv itli Imi ning and |ieieima al 11 it' site ol iU|eelinn lias Ireen noted with lit \t 1,1 1 iitlo]ililelutis associated with path be mappropr vidttal tumor liesponse r, nun ki ll t tut rims li\ |Hipl.i-i,i Tim Imm- lor llu- all ns\ ncratic rt'.H'tinn is lint understood. unuse u! IU \t mav eaiise ]>ernianent loss of veinj at avlmiiustiatmii sites btociiion as ns lows (jttnpli ( tit 1)11Liti\t marrow elicits are iiumlesteil lis low er tiatlirs at a given dose level, earlier appe.tratite nl nadirs lunger duration nl inannvv suppifssinti a in I a v ei aUe uai In s al a low ei level '' \ Iiiiu;iessiv i anemia in.tv I noleil alter e.u li i muse vt 1111 lailme nl (lie lieintvuliiliin level tn rise Link to its liaselme Tills iettaeltirv alleluia mat lie mini mi/eil I iv spat int; mtii m hii ea ei mi ses I in l tier a pal I ()l letfiil eoneern is the pulmtmurv tovieitv ,,( IK Nl and pmlialilv metlivl (!(!\l ). not viir. pil-inn Imwevei Iteeaiise the potential lor pro. di it int; I il hi ms i .I the It mi; vv as until I in t Ions during the initial develnpinent ol IK.Nl (llinieal sv mploms iisuallv im-little progressive dvspnea and tlironit nonproductive cough. whileehevt v-ravv u veal mleistitial ml iItiales w Inch mav lie pateln ihsappearanc lignant dtseaiiialigiumt Itpenis sstth Ik tint) ol all Ik tn greater than i it t nl the tvv. mass lasting I. i h vv eeks latliel tliun It vt eek-i anil mav let pill e let I m dil I use I'a I In ill mu evauiin.il ion ol I lie lung re- lilimtl i I'll 11 a list llslolls It i- essential t li.lt i ollipli It t ea Is a nons|N'i dit | iiilim m.ti v I iluosis and alveolar I tin 11 i minis lie i lieeketl at least om-e a vv eek tlili mi; cell dt sjilasia postulated to lie seeondarv to the al- ml I osi mi ea tliei apv pi >s-1111v t vv iee a vv eek in t lial kv latum aelinii ol nitrosoureas on respirator) epi- -nl>vittnip ol patients wliu'li inanilfsts Imtli e.nlv thelium Trim In the development ol lung Invieitv and lale nadirs In ft uni mint inn w il Ii i it lie i t lines m patleuts Iiav e geiieiailv let oiled I 1 g oi drug over l at I lot I lei apv t lie tli is. up - ol ml i ost mi ea slut nit I lie reduced It moi it Ijs to 1 v e.us The tin deal outcome IS vanal ile w it 11 let in ei v in some patients and progressive Tumor T (as||ii|ntes(in;tl Invieitv consists ol nausea and i espi i aim v I a dm e m ot iiei s I he role tit eortieo- v nunlinc 2 It Iioiiis altei atlmmist i at ion and pi i s| ei on) s m amelioialuig die pulinmiarv insuffi- ^voc-eat'c H -1st s lot up (n 2 f litu u s tt mav I iv soinevv li.it a int !- t n ut v indiH t tl liv mtro-nui'eas is unclear. cio"*-al itnuted In auticmetu s and lasting Tltis tovieitv i- N itrosoui'eas li.tv c hcen incriminated in the de- ea.i-' not v uinillative anil appeal- In lie eeiitiallv iiifd- vI'ltipiueiit o| t luninc n n.il lailme anti interstitial lOV-TTVi talt vI so t li.it it tine- ni it iiitei leie vv illi die alisi M'ptioii ol tile oi ,d inti osi mi ea- -v' I a111 a |iii lit side el 11'< I - 11a 11ide alo| ua ia -to matili- dtaiiliea anoiivia 11 v i a-il ile al an u mailt u - iiepin ill- ''1 11 \/oleima is geiierallv delavetl anti not asset talftl with III pel tension, proteinuria, or i a I hi mmaiv sediment aliiiot nullities Kitinev sire i- det iea-ed vt lute padmlogit evaunuatiou oiten _jv. in i-'stotog ijiioeia -s-he > 'tor nrsjgltiii $ |v ol 11 v ei t I leu list i ies 11 v pel e-l lie-i.i, ill//tile's a nt I tilsi lose- uloll lel nloselel o-t- severe till Utl.tr low gv net iiiiia-tia -s -1 IK \t uiav i a'i-e i imiiiiii 11v ai vv t ltd tii.'j . -I I la a |, an,! 'i! it lost mi 'il mi-1,111 uaiie OLI 7153 r ( \\( ||, ( ||\!` \ I ll-l\l s \\ il ihi PC') 101 "1(1 h\"I "Hi. -1 ``Uli "t \ t Ills ,l II v <.| "t M|r. >lu'"I illy him ,,| "'*i .tritl '`I.IU P-iP In* iiih ^i nl.ir 'Me lt\ iU over s Ml l i o-ssi\r Utii o. 'sill 1 I- In- (InIt l.i| d and i.l 0| nil,,, loss j mine dei:i er n| M led nil.11 \ mlei s| it ul hbt dms |n !1H < I 1,1 I MMI I *1 lllllnsnilh ,1 | { |l I 1 |I I < II I I 1.1 I i|U r is i n >1 k now n .i It I umu.h 11 t i,i | It i\n (I s v\ ,i s m preidinua\ trials in annuals f^n um"> "I ,icuU` imnlv nipli.H \ tu |(mik('ni'a ,< in ('ll I ep< II lr< I III | )a I H t il s 11 r,i I ( 11 w it li li'ii'J,IU nitiosniiMM lhei,ip\ Imi 111,mi nialiun meje\ >,i- pal lent n i I'luil I U \ l aln I (< \ 1 tini *1 In a IK-ill i ec el v rd 1 iirl li v I ( ,( , \ l \\ } a `I I a a tins nfrsrnts a v oim u'.enLd t mdmu m' nut is mu Irar prr^t 11 \nliiKO[)laslic ai'tiv iI\ l>\ Immir t\[)i`s ^ St \ ri a I t < mi | a eheiiM v e in lew s hj \ e I urn | ml)- 4u il t "iiu'i iiiiiU the cl Iev 1ivcm ss .Hid < 11nii ;iI ..4hnl IK \L 1 (,C\L . and mctl.vl CCM " ;sim|>ort.ml Id uvouni/c dial nitinsourcusan* w*l j ,c^aiil\ iutcicliauucalilc cDni|nmuds and dial r aidshtuliDii of one mtiosoiiiva lor .mothci ma\ < iruppi nprkite in the manauemeut nl an indtJual tuuiDi |tcs|Mhim* iales I<a nil11isonrcas .done ur m i omj iiatiun ms med in dm rc\ icu ate delmed as ioh | ns (.nmplete u^pouse i(.K' means complete 1 ,,ip|)eai;iiuc tor all climi.dlv measiirahlc ina- :,aiit diseiise without the development ol new jlninant lesions Lispin' Ini at least 4 weeks I\i,'iit > w ith bniiv 11 m last a ses in us| lia\ e normal i/a 1,iiiul all I m me \ i a \ s Pal I la I o sj h msc it'll) n lea ns aalei than oi e(|Mal to *)0\ deele.ise in the pi nd* kt nl t he l w D mealest jimpendieulars < t a tumor ! i.iss last n iu lor at le.N I w eeks w illn ait I he uu ir.tsr o| a li \ a o a ol k) ion 11 n la h^Man! disease i a die.ip| h ,iii,t t < a ii< w m ,e "I in iliiMiiinI iInmm' I oi Il \ i i u nl as| a si ` i | >a i I la I I es j h a ise l cl el s li, ,i )U\ Ol m ea tei dec lease in the sum ol the live) ed^e i ia asi n cn lent s taken I n 'low the ru^ht and lei t ( ost.i I Dial Un is in tin n s|m rpve in id < la\ let I la I I UK'S, and I m low I he ! ip ol t he v V piM nd ( )l >|e( 11 \ e l espouse mills |() | |,e sum ol complete and pal 1 la I l es| x mses I a hie Z le\ lews the published l espouse iates to the three dillereiit mtmsoureas m a v.meiv ol neo plasms \\ e w ill lt\ lew the i oininon tumor site's whole the nitios(Mueas ha\r been adeepiateK evaluated (i.islroinli-slinaI carcinoma (iastric carcinoma llic mi-d inn 'in v I \. 11 11II Hnsltu1 .it It t n h on-ti ii n i i;i 0 I (l 11 n it it I iv limn llic Iiiiic nl dm iiiinnl.il n m nl iti< i u .i I it 111 \ <)nl\ O', nl |i.ilnnls arc alive ;il I n .n \lllimi^h n I Iniilituiat d (n I'I ) lias Imrti cniiMiliicil 111 < si.mil.lid .iSiiiI Inr IrraluiU ndv.nici d Hnslric .iilciiiKarcinniiM nlijcclisc rcs|>nnsc r.itc` .in- mils In 20'i and arc slmrt lived Tlicre is nn snpal iennl dillcrcncc in survival in a lari'!' itriinp nl patients treated vvitli .Vlliioroiirai.il as compared In an untreated Urniip nitImn^li rc'.pnnili is li\n Innum '-ItnlliHC \( andmi llnl ( ( \l ai I-,ii 11\,1 .11^.1 nl' in u.i'l i ic i ai i mum.i u il li nlijcilnr inspniiM' tains nl IS', and I'>'. respm1 li i I\ and median iiur.it it ms nl respnnse nl 1 tin ml I is 1 ' ( ( \ I lias nn .nil i ill in Hasp u , arci- TABLE 2 1 f Tumor Type Objective Response Rates to Single-Agent Nitrosurea Chemotherapy BCNU CCNU Methyl CCNU No Ot No ol No ol No of No ol No ol Evaluable Responses'1 Evaluahle Responses Evaluable Responses Rets Patients (Si Pat.ents 1M Patients (m s-r-C O'M'K "Jj' ".inomj ; jil hiblologies - .^n.ioT cnoma - -^ins ,:r.HodgKin s ivmphoma 45 43. 44 46 43, 44. 47 46 49 43 44 50 1 4J 44 1 43 44 33 .5 l 69 76 132 83 69 213 107 6 13 00 7 10 16 21 22 13 9 11 32 46 94 44 30 23 1 1 0 0 15 4; i5 199 14 ; 166 170 20 12 100 ri3 17 13 108 279 46 16 341 73 27 37 27 34 40 48 74 52 13 35 57 2 13 2 13 18 1 t 44 18 17 33 10 6 22 19 26 10 18 - ;cr T DiuS y.H'tt'-'Cis VP-Ur.eO m fne ta*t :$()2 \ it 11 im mi ca*' hat/ (link TABLE 3 Prospective Randomized Studies ot 5-FluorouracitNitrosourea Combinations in Patients with Metastatic Gastric Cancer No of Evalu- No of able FeRets Patients spouse Percent' age Mi 'tii, in Unviv.il ( Illl.lllOM iiom itif Onset ot Che-Tio* therapy imonthsi 5-FU 47 28 8 PCNU 47 23 4 5 H) RCNU 47 u 14 Melhyl '.GNU 4 ;i7 `j-t-U + cn^lhyl 48 30 12 CCNU 23 7 4 17 3 5 A1 r i ii 30 40 50 umn.i \s single imttls IU SI .inti 1 < ( At ll.HlM IlimiUlal 11111>. I it I III Mil l II ,11 M till M.l VI l ( linii 5-1lunrmiraill .uni U(At> vvliru iim'iI in iiimliiuutiiin priHhlivd .1 higher rnlr 111 !\ I I'- tmnparrd In l-'l almii- \2t)`i ' nr IM At almir 1 I >' ) in patients w i < i i advaiii rtl gastrin I'.irniKidu ` and immsiimI>Ic mrl.nl.ilti- Imimis, Mrdiari sunn^ w.is ' 5 months lur IU AT, 7 4 months fur .Vfi .mil 7 7 niniillis Im the rmnlmialtmi (T;ihlc \\ llourvii tin (i ii n) nr i.it ii m o| .i It an,| |K ;\(- Mi|ii'iiin in "i I I ,il ,i sl.ilistii .ills signiliejnl l<*v*4 i nils ,il IS tin ml Its limn till- start nl Ihr-rapv with 21)' ol tin- |i;ition|s n-ivn im; tlm c iinihniiitioii 4|w* i mii|i,iii'il to 7'> w ilh .7-1 limmuraeil alone ">i The pastern ( 7h>|xT;itIv Onenlngv (Irimp ildfK.l om 111 ta mi I 5-IT anil mclhvl C<.\1 rmnliination i heniollii'rapy versus metli\ | (;( alone in |lain nls vuth advanced tneasnrahle {tistrtr inlieei and deinonslrated a slalistienllv vnmtliijiit Mtiviv.d ini|iioveinenl and response rate for ||,,. i m ii an,it ion 11 In |>alieii|s with nunmea'UirabU on last.ilie gastric i an inmna, 5-1'4 alon<` and .VFL' pins niellis I ('( At produced ei|iiivalenl survt\a) rates ol Ii > inmilhs from (lie ousel of therapv (nj meentlv reported VX'XH', study " It should he emphasized that the elleetiveness of IS-KL'-nitrtv soiiiea therapy lias Iv-en demonstrated only for that selec t |Kiptilutiori of gastric cancer patients who have advanced measurable metastatic disease Holh the (hislroiiitestinal rumor Studs Croup Croup methy (mills v detent U in' avhl i ti' going i Colore Pat i' medial proofi to sing! is to- 2 in the s appear used ul lUAl c,i:nc (T.M. Prosf TABLE 4 Prospective Randomized Studies of 5-Fluorouracil-Nitrosourea Combinations in Patients with Advanced Large Bowel Cancer Institution (Refs i Ijniv Pretoria 1641 HVOG (65t m.i. i' riuiic Chemotherapy3 No of Evaluable Patients No ot Responses Percentage Median Survival Duration of All Patients Irom Onset ot Chemotherapy (months) MU 5-FU + MeCCNU + VCR 5-FU 5-FU + MeCCNU -F VCR 5-FU 5-FU + MeCCNU 5-FU + MeCCNU 5-Fll 4 MeC-fNlI t V( P. 5-FU t MeCCNU + OTIC 5-FU + MeCCNU + VCR + DTIC 5-F(J + hydrOxyuren 5-Fll 1 MeCCNU 54 U t MevtNU 4 MtR-BCG 5-FU 4 MeCCNU 4 VCR 5-FU t MeCCNU F VCR + MER-BCG 41 39 45 46 42 152 88 83 71 73 M 31 32 a 17 10 17 4 48 9 Ilf 14 it 15 7 3 6 9 19 43 22 37 9 32 10 i;1 14 15 ?! ') 10 19 28 1 No - | ditlerence 65 78 - 1 No - ) difference 60 73 9! 90 73 ) 1 No j difference -7 v Nl - T U' n 1 i<- '''(' 5 hnr'lMvl it ,.-i'C '(TMi.Ll* >t .r,i Si ?,(P "t = 'Dtf'hTn' a. Sidney F, 170) Massnchi |7U Geismger 5 (721 Georgetow >66) Memorial-' |73l Memorial ,74J c itoneron w 51 i mVOG I ,76, J C^lGB | (77) ; ' L#-f ,f,cr 9e __ Juroiion Gr'S^ 0t no Lf1 r1 < \\i i h ( i imi \i I r.i \i s miri l')7') !,,riiii|>'" ' K.ITS(.I .uni ||m- Siiulliwusl Oiii "In4\ 11; ri >" |1 ,S iS\M)(,| .nr riiiii-nlK sludsiuU > l`I Kn'tlnl (.(.\U dru^-suntjiimin ri'i'imi'ii'. m p.iLnts with metastatiy nnstrir ijryiliumM In Ix'UfT I lt'|iTI II111*' I In' i I I cuts mi | uhi nl mii \ | \ .il \ Imi ini Lniim i' -I ('I'l'Sd adjuvant ihI\ t-iin11i.iii1114 ")lyl -uuthsl ( .( ,M I ivmliiii.ilinn thumps In nn jJlllljnM.il ihutaps III .1 Ulnnp nl p.ilii'iits llllfli't ii,ui)i uurahse snrjicrv Ini u.imiu- tamer folori'C'lal carcinoma I'.llieMls \\ 1111 ralrliinina n| 11 u inlnn liasc a mriliali survival nl 7 0 nmnllis I rum tIlf limn nl priml nt mcur.ilnhts 11 I In-uliii'chse icsImiiim' rain l,i .mull' a 4i'Ml 5 I11 in .iik .nit n! rnlnii'rtjl i-alii't'i ,i 15- 20' i \\ il li a 11 mill si in i pi nn a in 'ill ill Mil's Ival nillw mi mil urmip nl rt'S|*imlcrs Tim nitrosoureas i|i|M'ar In have limited thempenhe achsits win'll nv'il alnlli' w Mil obieelise H s|)onse rail's nl III1, I nr |j( M 7k Ini (f.\t, and Ilk Ini methyl ( ( Nl 1 ' 11 1,1 < Jhjeehse ri'spnnsr rales In meltis I I ( (M are higher in pres musk iinlrealed patienls u till ( nlm is 1.11 i .a miniii.i I tun iii pi es inns l realeiI pa hr n I s i 4 I k s i i sm p, i es[iet hs els I ''' I >i spile Inin inilial similes repnrliHU augmented response rales ss ith 5-IT metlis 1 ('('\l eoinlnn.ilinn i lieiunllirt.ipsl><> nsei 5 I I uluiie.vesei.il sill im-i|iii ill si ndii s ! us r I urn niul >le In ennl irm I lie ineieased lespnnse rale'" ""Those shldies wllleh SI el e pi ns| H'l 1 IS e and l.llldnilll/ed a I e si lllllliari/ed ill Talile l I lie tssn Mas n ('liiiie shldies are nl in terest because nl (lie failure nl one to Mipjxirt the Imdinjrsnl the ntlier. Meths I ( A !\l in enmlsinatmu ss itli 5-l'T alune nr ss ilh the addition of vini nshne and nr iininuuntheraps (ML Il-IK (.) did uni nnprnse res|xmse rales1'*' S\V<>(> comparing 5 I t plus iiielhs I ( it Nl' In .*-I't plus inilnmvcin ( nksetsetl irspnllsr lates nl |(>k selslls l Sk ' '' ' \lll1uu4h the .5-l't was given lis intravenous intusinn, the response rale tu 5-l'T' plus methvl (.(!\l was hall nl ss hat the initial SVVOC study'" tleinnusti,itetl In a snn'le-arin sluils h\ I lie Sidney I'arlier (lamer Institute, " 7>-1'l! plus methyl < 1( !Nl: produced a 1% res|xmse rate in 52 patients, larln'lnsv that of the other studies Other single-arm TABLE 5 Prospective Single Regimen Studies of 5-Fluorouracil-Nitrosourea Combinations in Patients with Advanced Large Bowel Cancer Institution iRefs 1 Chemotherapy' No o( Evaluable Patients No Ol Responses Percentage Median Survival Duration of all Patients from Onset of Chemotherapy (months) ;idner Farter Cancer Inst i70t Massachusetts, General Hosp 1* l' ijfisinqer Medical Ctr w 2i Georgetown unn 1661 wnoual Sloan Kettering |73l `.'s'.jii.ii-Sionn Kettering .74. ."Oerrult Univ ,'5i s.vor, n6i C'MGB 5-FU + MeCCNU 5-FU + MeCCNU 5-Kj + MeCCNU 5-FU + MeCCNU + VCR 5-FU + MeCCNU (single dosel + VCR 5-FU + MeCCNU (divided dose) + VCR 5-FU + MeCCNU 4 VCR F streptoiotocm 5-FU + MeCCNU + VCR + mitomycin 5-1-Lt t MeCCNU t B.iket s antdoi 5-FU + MeCCNU + daunomycm 52 22 36 25 32 35 54 19 31 17 2 2 6 10 3 4 15 2 6 5 4 90 916 40 80 9 1 M0 11 j difference 27 H 45 19 19 -- 1 " *i .:< 10 ' i`;ie I ;*04 Nitrosoureas kat/ (> 1 ic k stU(!i<*s .or mumn.in/i'<l in 1 a!dr >, .in<I aImml<'lli- (Mist rate loss response rates lor '>-1' l nit n ismit ru combination rlieinotlirrapv m patients u ith larijr lx>\\el canter Tlir lomlim.ilmn nl phi1' mrlliv I ( ( M sJk hi If I fir it } h ' < i tiiMt l< *H < I slant) ml llr.itniclil I of colon ( lal rao iikimu p.ilirnls U t .him il lias Hot been shown to i vpi o<liK 11 >1 \ ailUinont nsponsc rale4'. has ne\n horn drthonstialrd to iturrasr median siir\ nul over o-l'l alone and has caused ^iraler to\K'it\ ill.in loi 'uii'le^iUcht VII Tin* (dTS(; m an fin-uoim; spu!\ is romparmg the eflrct ol jiljmant VI'l plus motli\l (!(!Nl \`|M|S Ml K ] >< '< * I III milHol lit T.i 11\ ' < `| s|| s V|( Iiliis im(li \ I ( < \I plte Ml P |i( ( , In .1 tin I I e.il mi ill i nulli il ii iii iii patients w il li Dukes Uj .mil ( ' lesions Ini low mg i`i il .il i \ n surgi-rs Willi ,i mi'll kill Inllim -up tilin' ul I 3 tin mill'', there is nn statistically 'ii'iiilii'.ml ililIiti iu i` in treatment umn u illi 11 - U;ir<I (n limn nl ririini-nir nr sms is .il Scseral other .111111 \ .ml pi ospui'l is u i .mi Inim/ni I huls mi ni j in luting meths I <.( A l i hrmnlheiupv me iinilci s\us in patients \\ 11111 nlorcctal carcinoma lint results arc linl available a' set Pancreatic carcinoma llm median suiiii.il Irnm llm tilin' nl ilni nini'iilalinn nl memalillltV nl pant tcalic ailchni arI'innma is 3,5 months w il li <ml\ S3 nl I lie patients alive at I scar.11 Kluorourueil produced a 153 nli|ccll\i' i espouse rate anil 2.5-mnnlli median dmatinn nl lesponse m patients with advanced j lam i eat m nainmnnia In a pins| mi I i\e mill n till-d sludv nl patients with tneasmalile dtsnasi- > II was a.ssneiateil with a 1(>3 objective resimnse rale B( IN L with no responses, and the eoinlmiation of 5-l' l anil lit INL" with a 333' resironse rate ' 1 he combination. howeser. was not sigml n antis su perior as compared to 5-I'T alone either m terms ol res| rouse rate or surs is a I In another pins|xi tise randomi/ed studs comparing 5-lt and III SI svith nr ssithout .spironolactone. res|rnnse lales Inr tile two-dnm sersiis the three-drug program si eu I li' i selsiis Hr, w ilh ineiall median sui vis als nl > I and llrmnulhs uni slatislmalls dll Iei rut and iml liellei than the nalmal liMois nl llm ih'i.i'i1'11 Itei i 111 11 si ills 111 im llm It ,< )< . m pal u ills ss il li nnnmeasiirallie adsaneed pani ie.itii' um inmii.i rescaled 3 5-nmnth median sursisal im patients II raled w il li 5 II alnne nr m i nml mini mi i with mrlhsll (.St ' \s single allruts, lit ,\t ( ( \( aid nn lh\ I ( ,( SI liasr lilllr ai lisils in pjnireji*' i an 11 ml 11.1 and are uni assm. latcd \s i i m [>rin nj I lllier gastrointestinal carcinomas I I SI lias h111111 d .u til ils m the Ire.itincnl ,4 paln'tils wilh si|iiamous till carimouia nf py. i-si ipliugiis and anus 1 ' The other nitrowiuri-us iml Incii adcipiali'ls csahlatcil in patients mill, these neoplasms \s single agents, nitrosoureas j^j ini .ii 11s its in hepatoma.1 ' hut the euinhiiutiiiti ,4 5 r'l and lit A l lias shown a 373 objective r^, s j it a isr i air m one sn irs ul 13 p.iheuls s\ ilk |irp^_ luma with lliirc paliculs icmaiuiug in cuiiipl,^, n imssiun Inr greater than 3 sears 1,1 Studies using nitrosoureas in patients with met. uslalic gastrointestinal neoplasms have demonsi i aleil del mile ai l is its lor these drugs. Since nli. (eelise tumor res|xmses are. in general, transient wilh nitrosoureas alone or In eoinlmiation, nitmsoureas should not be considered "standard" then aps for this group of malignancies. However, it h evident that resixinse rates are improved when nitrosoureas are combined with 5-fhmmuraci! Adjuvant trials are thus underway to assess the elled of nitrosourea chemotherapy on disease- free survival anil overall survival in high-risk patients undergoing curative surgery tor gastric, colon, or rectal carcinoma. Such trials are based upon cell kinetic studies in animal models which show that the chance of eradicating a tumor is greatest when llm Imnor |mpul,itIon Is small I patients I Jifferei | y\\ OG of 31'' Hlll and 27 Mel: chetm. ftspiin jdisit inelas hilltv blood stratii preve nersi Malignant melanoma Nitrosoureas have limited hut finite aclisits against malignant melanoma with cumutatisp objeitive res|xinse rates of 17-lb7c for RCAt. II 1-3'V fur (AAT, and 15-173 for methsl ((AC ls sl \S single agents |U AC and methsl (.(At nimpare lasoralils ssltli llie 2 i-24ri cu- nmlatlse ohjeetive response rate of imidazole car- Ixisanitde (OTIG) and eaeh apjiears to lie suixrior In (it \C A11 hi i igl i nitrnsuiire.is have lx*<.n iisi d ill eumhmalinn w ith 1)1 l(.. tlieie Is no evi dent e tu \1mh\ lli.lt I I ICM1 ( I Hill Hll.lt mils .IK* 11- ( .mils mi|x-i im ln 1) l K ! al<>m- |\(!()(i lias dem* onslrciU'i! overall objrctnt* ros[xinse rates of lf>rc w it 11 I) I'K ! all me I / < w itli I )1 l( . plus IK ,\L and a` ad tai tr< P1 ' < \ a in I 1 is 11 \i I 1.1 s I , W ini' i ! `1,' I Ida < ( \[ ihi ri jtK- used 1 ""-ill uf i ill tin eas have Ills ss |(|, li ,|V ||,,,j l.ltlull ,,f 1 1' * rc1 h lll'|M1>'lf)|,|,. Illl llu-t. lll`T||(i||. Hu r ii||. 1 IIIS|(M| n. mtro(I llier\t-r n ls il is hen "uracil ' tin' e(. -fret* fills * iliin, iir ''in cell 'vs that '* " lieu -c til Its 1 nl.iln c IK At. , `1`clhvl nii l 11\ I I c,,. ilc car: i| H TK if c Iiccii III I I V 'lumli ' ili-m-I I IK, l . .mil ,, vi it 11 1) I K plus 11H l In I (,( M I n .in i Hil.llllllllin/l'll I H I ispl 'll IV I slltlls I ( ( )( , |s iiiparing ini'llisI ( ( \l in Iss11 ilil letetil dosage diixhllcs versus moths I (X M 1)1 K, jilns lis.,,,vv nri'.i versus mi Ili\ I ( ( A l plus IK (, 11nli.il ,,|HIII'C 1 ill"' .11 C I I 2 I ` , '\ 11 11 III I .III \ . 1111.1 u*' I "I .^triple ilmn .ii in n* the uictlis U .( \t plus IK l, dll iiici moths I (X \l ili .in Snmhilli 11 ii ,',\()(i 11,1 S lll'llll illsl 1 .ill'll .1 J_I g i', nll|cl Im- le iiiisc I vile ill I tin-11 uni ii i i.iln in i il I) I !(, IK A l , ,111! \ incrixtino ii It 11 nr u il limit 1 lilnrprmnu/mc in jlients mtli advanced melanoma. mil vl.ilislit .1II1 Ilt-ri-nl from tlial nl DTK! alum-1'1''' Otlui ,\\()(> similes liaie ili-iiiinisli'ali-il n-spniisc rales 1 ;p, u illi DTK , IK M plus In ilinsi nreav'Si .i|H): 'ill1 mill III 11) plus i 1111 1 1 si 1 nes'' 1 til 11 )\ I, nil 27', mill Kill) plus l.(. Mt-lannina patielils si lit> respond ohjeclisols In In-ilintlicrapi live significantly longei Ilian 110111 v,|minlers, IS s- \ilmsnurcas liaie llieir greatest (lin ill against Is mpli mult- -ill H ill a neons, and skin irta'lases llnsscsci despili tin high It pit I snlunlits and alnlUi nl nilrnsnureas In truss the dnod-brum barrier lliere is im es idenei' demnn.liatnig till' cflci-tjieness nl nitrusuureas in cither j .iresenting nr inducing I In- icgicssmu nl central ;n'rsmis ss slctn nietaslascs Breast cancer ( simulative ii-pnrted nlijcctn c ii-s|innsc rates nl irru.st cancer to single-agent nilrusnurca therapy are 21b tor liCM,4' 12b InrCCM r and 4ft lor nelhs I (!(!\l lS Mellis I ( t A l is clcarls an 111ulne agent ill In east eaicmuma ( (At. haslieen .Indied 111 eniiiliuiatiuu ss ills ndiinuisciu in patielils with ads.lined Ineasl i.imet n-liaeluis In hut : 'iiunal niaiupulatiun and retractors to chemoj therapy mth c> clophosphamide, vincristine, methotrexate, 5-fluorouracil. anil prednisone s<)'91 dbiectivc response talcs nl 111 -1(1' hale Iiccii noted mth the combination nl (XAl plus ailrijiiisi in. hut the rate anil duration nl response sscre uis similar Ii > t hat seen ss it Ii ail 1 lains em alone In .1 Inn.id phase tl studs, the 1 01 nl>111.il0>11 nl adrumycin, BCNU, and cyclophosphamide pnxluced ,1 o()ri objective response rate`n However, other .Itlriamicm regimens give eipusalent nr hetlei u'spunse lates'"'1' I'lie use nl iiiliusnuiia-i unI.lining t nmhinulinn tlieraps in piesmusls un treated metastatic breast cancer needs to be ex plored further f iing cancer t uumlahic d,.I 1 suggests that (lie nit 1 osui 11 eax base Inuiled though delmite ailisits m patients ss ilh lung 1 aueei ss ith oseiall tesjhmse 1 ales nl II', nl IK \l ll,1. Im ( < At .mil III', I nr mil lis I It \t 111 W hen 1 espouse tales an-anals/eil In the spi 1 11 a Insl 1 i|ng\ nl I lie 1111111.11 s long neoplasm nnlienl I he 11111 nsuilt i as is elea I I s sn|iei!ui In alls ntliei liiliiisuiiiea 1 `` 11 laki-mse lesjsiiise lates lor ans 'ingle nit I osoiil ea ale ei|iilinh-|lt among the loin ma|oi Inslnlngie subls |)es oi limgeaneer I'lie ills, 1 ppi nut lligls loss 1 esj muse lates hale led In I lie UK orpoi at ion ol uitiosoureas into combination I egunetis I he \ elei ins \dmunsl 1 at ion I mug ( uimp pioII m ol Q | | i mutinied esi lophosjihamide alone to i s 1 loplios| ilia mule plus (!(,\l , to adriamyciii phis ('( At and to adriamsein pins eyi lophosphamide in patielils ss ilh adsaneed broncliogeuic carcinoma using Sill s IS a I as an endpoint I'm patients ss ll II small 1 ell 1 .111 un nun huge cell i.iiiumina and adeuoeaieinotna ol the lung, the lour treatment arms appear similar ill lei ins ol both objective re sponse rales and median surs Is al 1st (Hi has compared meehlorelhainuie (nitro gen mustard) alone to mechlniolhunimc and <'( Al m a prnx|>ecliiels raiidomi/ed trial of paI uni s ss ilh adsaneed si pint nous eell t urc'moma and la 1 gc-i ell carcinoma ol the lung lint ss as unable to demonstrate alts differences 111 response rate or surs isal betxseen the tsvo anus.'1. In a second prospeetise randouii/ed studs. It ()(! coin pa red es clnpliosphuuude alone to c> 1 lophosphamide plus (!( Al m patients ss it 11 nils a in 1 -it small eell i .111 mount and .idem m an mom a ot the lung l'' l or |ialicnts ss itli metastatic small-cell carcinoma objective response rates ssere 43b for es clophosphamide plus(!(Al: compared to 22b Im i si lophosphamide alone I loss ever, a statist It alls significant survival advantage among re sponder, i mild not he demonstrated for the tssod 11 ig lombmalion Ini patients ssitli adsaneed ,uleimi a11 iiioma ol the lung, objective iesjion.se lates were the same l 12b ) tor both chemotherapy legnnens a' ssas the median survival lor the si ibgl'i nip "I | espi ilillel s Ilia thud piosj ieet is e studs h (.( K . is com pa I mg m pa 1 ii tils vsilh loeali/ed small-iell carcinoma i ad i.i I nil i to the pi in lars tumor and draining nodes alone seisiis ladiatiou to the primars plus cycln- lOti Nitm-mircas K.it/ (.lii k phnSpll.lUlldc ,111(1 C( Nl W|sl,i ladl.ltlnil I,, ||,, pnmms and 4i.nti.tl madialinn tcisus ,, 1 f ihne modal it ins {11111jj; and ( i a Dial il r;t<I j.it n in plus chc- motherapv),|'1 bails insults suggest ,i |mismId(` 1 mnel it int the r.uhnlhciapt .ti iii'. in let Mis (il pie \ I'll! inu I il .mi met a si a vs hnl (it 11 hi lei i nit ,is v cl ill mciall .nihlinnin I nspi inscs ( A rl< >pll( ispll.lllhi li plus mi I In il i ( vale 11,is lii-nll compared prns|>ectl\el\ h' n i Inplmspli.uiinln n ii `I I ml I (` \n In, inn) ( CN 1 m ,t \. limit, i| ( .auccl Institute \ A ()ncolot;\ IK,inch pioloinl I'm' patients \\ it 11 adeiiocaicllinmu. llm tluec-drug ann was statistically Mi|M'rmr to llm tssn-dnig arm ss illi regard In objective res|xitise rain (3Sb n-rtin Hh ) and median sm s is al I (i 7 \ctmis I U nn ml In) I m pallnlits \s it It small cell i a I (limn la, llm I In nn dull; regimen pmduced a longer smtital Ilian Inr the two-drug regimen hnl this ttas imt statistically significant I nr Irnth adetincaicmoina and .small- cell lartnmnia, rns|mndnrs in lintli anus litnd hnicer llian nnni'i-sptmdnis Nn Imatinniil adtain tage 11 mid I m slmvvn Ini pal milts with si |uanmns cell nr large-cell iindillcmnlialnd carcinoma (>1 iiili rnst IS llm pieliituuais reporl lit I're- sanl1"1 ttlin reported nn a pilot slndt nl amplm- Im inin II and (.( \ t in bronchogenic naimnr t a lls treated w ith amphotericin hat e enliain ed uptake (i| ii ills as tt ell as lai nr and small nmleenles. and this I hei n el li all t nnahles nn tie dine In enter llm t ell 'I lint lie.ilnd II patients tt illi anmplmlt I n ill plus BCNl and dneinnented live nhjeelive resjinnses lasting I 5 12* months These authors sulisci|ueiills re|mrted on a enmhinatinn nl amphotericin. adri- aintt m IK Nl and nsnlnphnspliamide ill patients J net mllsh I nsislanl In I Im la I let I III nn (I I Ugs ll>'' \(1 lespnnsns well1 sntai in llnnn p.lllnnls wllh llllin t ant in lint a t (an pint e inimssmn tt as snnn m nim patient tt ith at nle inteloinounettit leukemia nim pailial ies|nurse ttas seen in multiple mteloma. and one pailial lespniise ttas unled in Innas! raneei The optimal role nl liitrnsnureas in the treatment i>! limn cancer remnins In lie delitied, hut the promising results in animal tinnni nmdels hate iml Ih-i-ii continued m man (X \l ap|>e,ii' In meiease ies|mnse rales in siuall-eell carcinoma hut has not t nnsislentlt lieen slant n In pinlong survival A nniuhni nl mmniil lulled studies tt hit'll unhide a nil i nsnuma as pal t nl a Inin - nl I it e ill i u I egimen hate laded In ideulilt the advantages nl mlm- snuie.is in the lieatinent nl patients tt illi adtaneed lung cancer "" Primary hrain tumors Malignant gliomas S|||( c lilt- propel it nl lipid snhiliihtt JM'rrtuttthp mlinsnineas to i mss llm IiIikkI hiain hairier thr^ (11ugs hate uudeituine nnmeiniis trials pnuiait icnliai uei t mis st stem tumors snirrstK astrnt thimas and malignant gliomas) l(l" ns ^ s|amse 1,lies III (lieninlherapt trials have horn 4v scssed in the lileralure ht a decrease in turner i|j* as documented h\ hrain scan tund more recentlt ht computerized axial tomographs) in t't>njiim-tio*i with serial neurologic examinations However ,, IS app.neiil that ies|mnse lates In nitrosoitrcas arr dil I mull in determine since mans patients are re ceiving concomitant steroids and have received radiotherapy nr undergone surgery in dov teni- poral relationship to the use of a nitrosourea Initial pioneering work at the Iniversitv nl (..diloiuia at San I'l.mi isto 11 (ISh ) in |iatients with iei mien! malignant gliomas demonstrated Jn impressive 7)1''. (22/ 13) rcs|>onsc rate for HCNT' and 1)*< (10 23) res|}ome rate for jn l)n_ emit ii died (rials"" 111 As reported, cumulative literature response rates are similar, HOM 44. Ih'< 1 ,l* ('( M f7*( .l! inethsl CONI' 22rH' ( nmbmalion o-gimeus hate also hern etplureil jn imeooliolled Minis at t < (N(' ill the treatment ,,{ patients tt till iei in lent in a I igi la tit gliomas ""ill: In res|Kinders and "prnliahlc i'es|inndi-rs. response rales nl 4T'( (21 -In patients) hate been achieved with HOM plus prmarlia/iue, 4l'i iT, IT! with IK M pins vincristine. -T1'. tt) 20' with l)C\t plus A 11 non an .14 11, and tit)'. ( 1S 301 w il It ( (,\^ plus tmeiisline plus proemha/iue Median dura, linns nl lesponsc in unei|tnvin al res|Minders )ia>c Ucii 7 I, 7. and 0 months, res|Hvlively. hut are not supei mr In |1( .M alone (9 months) or CONI, alone ill iiioiiths) At llm Itnssvell Park Memorial Institute 2<> ol 50 uonirradiuted patients ssilh netvlt dim- nosed gliomas placed on combination chemotlier- .11>s with nicllitl (.(.NO, proriirha/tur. and van. viislmc showed objective res|)oii.ses Tlitrlceit patients remain in remission from (i In r>p+ mouths The Hi inn liimoi Studs Crimp (HTSCt in j pins|K'i Use taudotmyed trial compared sup|Kirtitc lheia|it alone IK \t alulic w luilc liralll irradij. I mu (.5000 (itKKI rads| alone, and tninhined IK.M |ilus whole Ilium irradiation i'KHM) tiOtK) rue Is) u, patient Mirtiie. nf the ' 503 prolm In.ihlc .malt / and o vurt it vi celts 10-3 ss active care a radint1 virnup ,.l the ticallv result' (linin' is con prospe 81 B Br. K ) up: I ( s\< i i< ( i imi si 'I hi w s U niter l`)7lf ;i<)7 rs lv l**Ti?iiistl*. Imi|UT. lllov* ``U.IIIIH "'"'s IiiiomIv ,v, Me, K(^ Im'oii 111 luin.ir ili,, ""< recently 1 '""illllllKK, 1 hisseser, j, "-"iircui I 'cuts arc re''' ''(.(nod " 1 l,,v<` term 'vnuroa "iM'rsin of ,:ll'eri|,v u i(f, ""'rated an lor IKM in urj* ''""iilalivf ll( M 44- M 22T m 'hired in *' 'Hi-Ill ,,f 'III.IS l"1> II' II -n In.'s,.,! I ! ss it!, ill. IU:\i "li (:< \i `I'.iii ilur.i"I' ts ||;U(. ' '"I *irr lint 'l"f .ilon,. I hiMilute " I' 'lian'iiimlliCf. uni \l||. I 11111.'.*,i ' I" >0+ 'MU It, ,, "I'I'orlis,. " " i.nltj. d iw :\ i I rads) in al ii i its ss It li r i i.i I |o i ui i it id mm,. I. .11. ns mu del mil is > .ufpieal inters el it n in iisini* siirs ival as the endpoint ,! tin' studs '1 1 (Tallin li) T\s. 11 n n id red tss .ails -tss. i ,( o(t'> patients entered in tin- studs satisln d the ir.il.H.il re(|iiireiiicnls and sscic eniisnleied esa !il,.l lie Will'll tile ,iilc.|iiatfl\ llealed pinup ss as eo.iIs zed (11 i.it is, pal a - nl s ss In i., s eis. I '. it M X11 ads j,n! nl Isso ill mine e.nnscs .il |t( ,\l ) mrdiali ,i,rs is a Is ss ere I , 0 ssccks Ini suppot lisc s aie 1) 0 [s.eks Inr H('Nt , 37 o ss eeks lor indictheraps and til a ss eeks Inr IU t plus tadiollieraps \ll thine jilisc Irealiiienl arms sseie sii|M imr In siippmtisc , jre alone \lllmut;li I lie median sm s is a Is . .1 I lie Milmllieraps alone sersiis radmllieraps plus lit XI ,;riiiips ssere iiul dilleieul tlie IS-nmiilli siirsis.il ,,f I lie i a 1111 >1 liei aps |ilus lit \l i;i. >up ss as s|,.l is Ui.ills superior to tile radnillierups j;roiip I lie results of tlie second and (lin'd I3TS(I trials are .iiiliin.iri/eil in Tallin ti A loinlli studs iniderssas ,, iom])avin\; simulat'd ssliole hr.tin iadiollieiaps plus lit ,NI ss hole liiaili radmllieraps phis stopIn/otm m, ss hole I tram radio! he laps plus the rad ioseiis||i/er, misoiiid.i/ole, lollosved Its lit .XL, and laslls siiperl rantloiialion radiotherapy, I lie I t t )(. li |t)t; has lepoited pi'climiu.il'S 11 si 1 It s ol a pins|teelise liial ss 111. Il lalidnuii/cd pal i.i its ss il h e.1 a. le i and I gliomas l ol loss ini' op(I r 11 a I simps,il inlei s enl mu to ssliole liiaili radiotheiaps ttstKKI lads), ssliole Itrain radiolheraps plus a HKHt-rud Uxister dose, ss hole Itrain radiotheraps plus Iit:\t , and ssliole lirain radiolheraps plus mellisl tit,XI plus DTK.11'' Willi short-term lolloss - up os eiall me. hail surs isal is 3N ss eeks and is similar lor the lour treatment arms, hut these icsults ale | ti el i 1111 na r s I sso additional latulomi/ed studies ale suntmari/ed m Tallin ti and tail to slioss an advantage lor the addition of ehemotherapy to suryery plus radiolheraps in terms ol patient survival Not slioss ii in l ahle It is a leeenlls rc|xirtcd ioo[>crntivc TABLE 6 Prospective Randomized Trials of Nitrosoureas in Combination with Surgery/Radiotherapy in the Treatment of Patients with Malignant Glioma Reterence Treatment No of Evaluable Cases Median Survival (week si Brain Tumor Study Group114 buui^ry IciUow^l hv Tumof $!udy GfOup115 Suraery followed by Tumor Study Group* Surgery, followed by M,i,o Clinic ' Surgery, followed by Milan"" Siugeiy followed by **' r.ititji if'AOtai'on Supportive care only XRT" BCNU XRT BCNU XRT Methyl CCNU XHT t mcitiyl U_,NU XRT + BCNU XRT + procarbazine XRT + methylpredmsolone 1 XRT + BCNU > XRT + BCNU + methylprednisoione f XRT CCNU XRT + CCNU XRT XRT i BCNU XRT + CCNU 170 TOO 37 5 25 0 40 5 36 0 33? 31 0 310 510 Arms remain coded with 326 median survival ol 40-49 weeks 22 50 0 22 28 0 19 52 0 32 46 0 34 52 0 36 69 0 ,10'S \0rosnuriu'. k.il/ I :iirn|H\m Inal htmi lhr \ OU l (. lit.tin I iiinni t r 11 i i f > (uih|Miiu^ piihcnl's In.ilrd witli MM'HTV | >11 IS l*ulutlii`M|)\ |>l'is { ( \l U iMllt .ip pro\im;i(rl\ -1 w<vLs Miu;n\ i r.nU (.(Al ) u it h a maUlu'd <jiutip m wliom < < M u as I>i11\ a! In himn pit^u,^nn \s a - in 0mI I !al<` (,H\l ) |JU I'l ' t M( l V, ( <'\l "lUlipitl 12 i \-i hi.il iji - p,iln hK Ii.mI i 1111 `i 11 a m sin v i v \\ hum Mil Ur i s nl ).'l a n|vs in il slal M n .ilk i III In ml limn ll.r "lair" C(.M HHMip III >0 ex ,| | ll.ll lit1 patient' XS llicll liad II mo I Lit I slll'x |\ ;|| III 02 M 111' ( urrrnlly il appears Ili.it III tlx* uun.iHemeiit nl palientx with 111.111 r i. 1111 nlmni.ix, I n mI iiiiiiK lli.it emplox sur^erx plus cranial radiolhci.ips (xxitlinr xs il limit :i nil lost mi ea ) are Mi|inmi (., 11 oil incuts llml rmpliiy ini(rii plus .1 111111 ini>111 1 issillimil radiotherapy ) \ 11 i ii it nil 1 11 ill 11,1 iiiroo ,i It >t u- .ire clearlv active m patients with recurrent ulinnia, tlieir role ill imlia) treatment as pait ol combined mndahls theraps lemaliis unclear lull ini|n l nils will lie eliuidatol through pins|H elise trials llial timtriil Imtli sternid and radiation doses \ higher proportion of IH-month survivors has Ix-eri noted m patients rcccismt; radiotherapy phis BdNC Medulloblastoma and epends inoma The eomhiriation ol ( C\C plus vuierisline plus procarbazine has lieen used in pilot studies lur the treatment nl poslirradialmn recurrent motulln Mastoma with a Wi (7 12) res|xmse rate and 10-month mesltan duration of response IIIS Ufl Scsere niselotosieits has Ixi'ii a ma|or problem in this studs proliahls Ixx nuse nl the prior eslonsno ceii'lual anil spinal axis uradiatioii I lie ( lull 11 in s ( lam ci St ill I \ t ii imp I ( ( ,S(.) is presently studx um the cflicas s ol combined mo dality therapy in patients w illi medullohlaslomas and iniratentorial e|x`nds iiminas \ll untreated patients recede postoperatisc radiotherapx to the entire cerebrospinal axis w ith a Ixxistcr dose ol ra diation to the jxislerior lossa I lall ol the patients are randonii/ed to l oiieuncut w eel,Is s mi l 1st me lor H weeks lollossed lis ell'll! 0-week cscles o| eomhination chemotherapy ssitli CC.M., predni sone, and sineristine. In .1 srrond studs patients sslio base relapsed lullnssuiH sioneis and i.alio theraps are crosses 1 osei to treatment ssitli ( ( Nt . \ 1111 11 ,t 1 tie and poK-arlta/iiie, ss liile llmse idapsimi alln sin Hers, i.ulintlietaps. and ehrinotliei .ips are 1 rossed user to treatment ss ith pHxarlia/inc alone \ddil n m. 11 1.idiot hri a | is is Hisrn il tin- rrljp*. |Wt oi riu n d Hi rain lli.m I srai I min di.iHimsn y dalI I III 1 r IS no dll In rnee lirl w rru till- Ism rt*g| 'm il'' in Inins nl discast-lrre sursisal ur <iseraJJ sin s is al Multiple myeloma \it 11isimii-.is hasr lirru studird in multiply, msrlom.i as part ol initial remission induction thri.ips. ill patients who hail late relapses following "li|rrtisr remissions ssitli standard alk\ latim; sorli as I plinis lalaomr mustard (mrlphalan) or rsi Iii| 1I11 ispliamidr and in patients who base n,.w.f H-mird all initial nlijrrlivr rrs|Miiisr tn di,^, ill iihs ( .iiieeraud U ule 1 .eukemia (.mop It (C\LGRi romparuiH IK AT plus prednisone to meiphalan plus pirduisour uidurtioii tlier.ips, noted an espial 1 rs| n nisr m Iml 11 hi mips i It)11 s r 1 si is I I1 V ) w i(|| an osnall uirdiuii 'ill \ isal lor the irs|Mi|i<lers of ,`to months luci'ea-cd marross tosicits in the B()\l -prednisone arm in conjunction with the lossn rosl .mil ease ol administration of nielphi- 1a 11 pirdmsimr make the latter arm more preferalilr The rivnil 001 it K(X)() Southeast Group studs romp.iiitiH IK Al -cs 1 lophusphamideptrdiiisonr aH-on't mclplinlau-prrdntsotie in presiimsls nnliralril patients thus lar has slmssn no siipciiniits in Inins ol median sursisal in the (hive-dins; arm Similarly, the (.anadian \jtional Cancer Institute studs enmparinn cnmhinal mu melplulaii 1 s, lophosphamide li(At lltid piedniwme mduetioii theraps lor presiousls on. Iie.ileil m\ eiiuiia patients to melplialan piehtiisniH. alone I ms show n 110 sihiiiI leant dll leieiue in terms ol median stirs isal amnuj' the xlillcrcnt treatment Hroiips ' In an imeontrolled studs al Memorial llospitjj usiiiH a lise-druH regimen ol melplialan, cvcln- phospliamide, IKAC. prednisone, arid vincristine 1 \1j protocol), objeclise remissions ssere obtained m IP Iti (STS I milrr.ilrd mseloui.i patients ssith a median duration ol rcs|Xuise ol 20+ months and -in c\|X`ctod median surs is al of 3-1 + months lr' In addition 1 > 20 t.70' 1 ) previous "failures" ssere 1 epi a led to lespond xs it Ii a media 11 1e-| h mse 1I111.1111 >11 ol 22+ months ItenusMiin m.imleiiani e xxilli IK \l nr niclphalan Im patients xs ho enter "complete remissinn idelmed as nreater than 7.V( tumor regression) was stushed I noted th statistical to niamti plus pre< The T' therapy occasion lunation isinil Th treat IT sx ho xs S t jlks lalii the 13 clinical lion in t others h tumor r pam SVVO eonibin cristine lapsed therapy remissK 20 p.ttn csslopl remissn ,ei uin urinary ,ix pal treatin' chetnoi llntia nllrtisou noted in detmesl as sec tivatin Is mph these mot he x imisb eslalil1 CCM Tin I ' '''I'M' lias 7""S|S To regi"'rrall multiple "idnet inn ' 'll"" ing 1 '"U agents 'balanl ,,r '.nc IlCSer l liesc ( \i.c;n, ""ll'lialan 'I equal ' ' " 'III an ill is n| :'j() 1' i" the 1 "Uli t|u. 'I uiclpha'if prolera'l (.roup ph.unidc''if m pre- n no ''I in llif ailian \4iig fotnlnX Nl anil ImisK ,ln. I "f'lnisonf '' m Ifrnis ! i f! 111 ifn I 'I l"'pilal Ian f\,|,,. Mllfllsll,,,. ' "lilanifil 1 ii " ill, "11111 is and Mil lis > | ,, Ilfs \\ ( | o i MISi ill,,,. I "I 1111 | II llllssll m '"ion) was ( IMIII ( M mi \i Tut MS Winter, 1979 :109 .nulled In \lf vainaii fl al m llif S\\ <>< . 1 I In-' Inull'll tlial ifinissnin ilnralion and smsis.il weie .talibtiL-u 11 \ identical in patifnls randoinl' assigned to maintfilanfc niflplialan pins pifdnisonf IK Al plus prednisone. or no liulhet lifatnifiil I 1 n ifsponsf lalf In single am'lll ml 11 isi nil fa ,|if i a | n ill it 11 a i It n s on i * Ii nn a |s In nitfi I In an iH'ca'ional ill am.it if i ospi inso llnssesti lln imii nutation ol IKAl plus adi'iauis t in mas I if prnin- 1 .siilU Tins fiMill>ination was used in a pilot studs to iinit Id pat nnils u |ni did mil IfspiMill inillalK in ] nlio wen1 in relapse allfi ifinission piodtitfil In jlkv lat Iim agent- prfdlnsiMif llif rap' Si-icm III lif Id patients responded. ssith complete Jink al remissions .mil a gi t aim Ilian 7.V. ieilin null 111 liimnr cell mass lasting 12 II) inniillis TTsi atliers liarl partial remission \s i111 lesser degrees ol , minor mass rednetion and iniprinement in Imiiio . I1-1111 S\\ ()(; is mini nils evaluating a lonr-diug eiii ilii i lain mi regimen ol IK At. aili i.imscm, s m(risline. and piednisniie in patients \s 1 ni liave tcl,i|isfil on niflplialan anil m e\elopliospliainide (lieiapi and in pain ills ss I in nmei achiesi d mili.il ifiinsMon illi standard alks lalmg dings l-~ l-s < >1 T! p.ilienls " Iui 1 tail relapsed on niepllalaii and in oelopliospliaimde.9 (>!'. I liase aeliie'ed a parlial IitMinssion as e\ nletn ed 1 >\ >n<)% decrease in llic .i iinn p.naptolmn m a dm lease m Heme |nnes hi in.n \ pi olein In less 111,m JIKI mg | xm 2 I I mins t )l ms p.ilienls nevei "'ponding In eiinsentnni.il lri .itmi Fit one lias ri'ponded In tin i|ii.idrnpii i limmillieraps regimen ' Lymphomas Inili.d " polls ol I lie an! il mnor ael is it \ ol tin- nitios.Miieas m malignant Ismplionia "me Inst Milled ill ItM).") I is DcNil.i-'1 l lie lolloss mg decade , !r111 ni I a 11 im,11 imil le 11 ile I in IKAl and ((INI ,is seeondars notlu'i'iiii- agenls in llie lualmenl ol Uilli I Imlgkm s and non Hodgkins Is inplioma ( ilimral trials aimed a I i in orpin a I mu these nitrosoureas mto iiulial fomliinalnm i lie iitollieraps regimens liase lieeti instituted m pre- suuIsis untreated patients, lint llie results lusr mg Hal ill si led a del mil is e role lor ml herIK IN I Ol ( (At in pi imai s 11 eat mm it i cgmn us ml o ism in-as u i pi i s loilsls pealed | Ir k Ijgk 111 s disease .He t ('. Im IK N ( IS', lorCCNt Maml 20% lor nu tlis I (X At 11 (lamer and Acute Leukemia (.roup B i (! \ I.(!|T direct Is compared the eftuacv ol ( ( At versus |t( Al ill patients ss itli advanced 11 ml gk m s d ora a1 ss ho ss m e i el I actors or mu c- spinels i Ii i pi n n i hen ml hm aps ' ' I In - overall re- spmisi In B( Al i _IN'. ol % IP patients) ssas sig- mlii antls less than (.( Al l7d% in It) 21 patients) Tvsenlv -tliiee pereelil ol the patients given (X AL n lues ml a i muplete remission Sequential trials of 1st INI ami moths I (XAL In llie Southeastern Oncology (I run p iSKO) have demonstrated inferior single-agent activity for methyl CCNL, and this agent is miss laiely used in the treatment of I lodgkin s disease 1 1,1 ()l interest is the recent re|)ort by Harrison ami \eiman,sl ssho used BCXL as initial single-agent chemotherapy for disseminated IIIB lone patient 1 and l\ B 110 patients) Hodgkin s disease (lomplete remissions ssere achievcsl in 7/11 patients ;md lim e are alive ami discasc-lrcc after 00. 77 ami 0 I mouths MOIT tmlrogmi mustard, vineristine, procar- Ii,i/ine. and prednisone) is (lie standard t!iera|)eutic' icgiim u lot piesiousls untreated patients with stage IIIIt and IV I lodgkin s disease 1There has Ihcii eonsulerahle iutertst in incorporating the nitrosoureas into newer combination regimens in an .illi nipt to pinsitlf all elleelise alternative to VIOIT I ((H. sinnp.Med MOPP to a live-drug legmien IK A IT IUAI s \ clophosphamide. s iiililaOii,. pen arha/ine and prednisone ill ad- s ,1 111 ml I lodgkin s disease ' ' There " a' no Si grill lean! difference between the induction programs in ai hies mg complete remissions (70% ss itli MOPP. 7.V. with IK A PI') Two-year durations ol com plete remissions were similar (MOPP 00%, BOVPP 7Ti ) as were 2-sear survivals (MOPP 77%, BCA'PP 7.V, ) Aoalssis ol llie mamlenaiiee |)hase shows similar 2-sear complete remission durations (IMA I'P 77%. B(X) 79%, no therapy 09%) and similar 2-vcar survivals (9017,, 89%, ami 90% rc- spettisels) Severe gastrointestinal toxicity and neurotoxicity xvas less with BCVPP induction al though hematologic toxicity xvas similar The SI X i achieved a 08% complete res|X)iise with IK \ I'P 1 Their initial data suggested that six .iihhliou.il eseles ol IK A I'P or MOPP clicmo- llnn.ips m patients achieving complete remission w .is advantageous ill terms ol increasing I mill dis eased rcc survival and overall survival However. Hodgkins rlisease l lie i mmil.itis e iepinted response rales lor llie :)l Nitrosoureas k.il/ (. I irk ,1 lucent 1 < ] M 1.11 <' '' teiu.ded nil Ul ll.1 III alp |n| iii,iiiiti,n^iti<^> I'lit^iitiiltn`t.ip\ 11\i11 i 'mi iminit i ihi 111 ils w I in wei i' iiiiin.iiiil.nl n-i I I ln'i i l.il.i i i ml n in tilt' results ol .i Nullmiul ( .mi cl 111'.lilntc li i.il \i Ini li ilnl uni ilemonsl rule ,i mlr lm iiniinlcii.incc i )ic- mnthcrups u it11 citlici \l< )IT m \\ itli Mimic agent IK \( in | ni I ici it ^ .illinium M( >IT iiiilin cil i i it 111 ill-I c icinliMiini 1 ' ( !( ,\ t Inn nisi i In cii ini i n | h ii .ilcil inti > I In lm t li m ciMnI>1 nil11<>ii ii'Hinicin lm pievumslv untie, I 11 patients lint lm.ll icmiIts li'nin these cnnlinllcil Inals ;n r | hi ilium I'l cliiiiin.il i i cm i Its I n mi ;i | ii i >s| h `i live ('.\1,(di studs ill | Ml tents mill I hi! 11 iiiilrc.ilcil .mil pi'ct imislv trcnlcil si,me III .mil l\ MimIl^Uiii siIjn- c.isc i mill in i itm NK 'I'l' I'l* 11 lit 11 mc> i niusl.ii 11 s inliliisluic. |)Hh .iiIm/iiic |uc(liiistiuc), ( ( Nt plus .................. (KIM1 plus \ IT liiivc suggested .i gienler numlx'i ul cmnplclc leiiussimis in t|ic "prior therapy " gimip receismg C -t INl cinnlii- 11. it li >i i llici.ipi :i.s iiiinp.iinl In nilumcii must.nil 1 III in lil it li ii i (!< ,M ci inl.nntim 11 mi 11 iciis w cl c ns socialetl with Immci ill.nnl,nncil icuussiims \ vaiiilv ul t.(.\l ciml.iinnm cuml)in.ilnms w itli adi i.imv i In. Iilemnv ciu i uilil.istinc, slieplo- /iitiH`i11. .mil prciliusinic liuic Ih'cii des eloped lm puticnls mtli \t( )IT-rcsist.int I lodgkin s disease They ucliicic p.irti.il remissions in 59 55', nl tlic pulients 1 1 - \HI 1-1 11)tlk ill's |\ llipllinil.ls lte|x>rted overall resfxms** rate'' lor tlic nitro soureas in noii-llixlgkin s Is mpliomas arc 25'\ I nr IK Nl 2Sr: |<trCCM n anil IS', lorindlnl t.(!Nl " IK A l lias Iiccii stiiilicil cslciisncli .is p. li I ill iinli.il i mill nil,it h in cliciinilliciapi iimuncns in previously iinlrcaleil patients | .( !(KI compared c\cliiplinspli.intiile preilmsoiie iiiiliietiun to lil At pieilnlsmic niiluclnm in puticnls w it 11 mnlul.il anil ilillusc well m pnmli ilit lei cut luted IwnpliiK-ytic ly mphoma anil demonstrated no smiiilienilt ilillcrcnccs in cmnplclc anil purli.il ic s| n ui.v rales.1 ** Tlic cmnplclc i espouse i nt,- u if li IK :\'U-prctlnismic nl IS1, was signilu mills mlcnor to tliut acliievcil with other non-nitrosourea cmiiliination regimens 111 In addition there was no i mss icsisl.mcc in those p,i (let it s who I ,n led in dm lion with citlici ngmiin, The I mil -ill ny emu I mini i, m nl IK AT liit \l i \ i lupin,sph.inml, i ini 11stitie, mid picdisonc) ,ip|H'aicd Mipeiiu, In chlor.inilinctl .done in the second or maintenance i ni l Ins I (.<)(. 11 ml I iv t In- hmhei pcrieutag^ ,| i i miplclc 11 spmiscs i ,1 ilnincd mid lew nr r,.|Mr* 11 he inlcnsiv c lil A I1 mm 11 ' In patients \m|| ui it 111 l.i i midi dmi 11i1 ist iIn.st, iihv lie clym.. phi oma, l;.( (j(; again ci .diluted IK AT and ui Ineved a infj,, ,,rk I iv innlti| jhilitv in l Urn I ^Lmirnssllaatlec prole Jjin_. a..n...dt to inti jcleotides I'h; plclc icniissnm i.itc in these nnlavur.ihle hivloU. tiles 1,1 I lie Sl'.l, uho si uihed |he lil. VI' cmuliirn. ipid gastrointe; scls, and eeri him in dil I use Inst n \ I ic l\ in pin mm achieving | .)()', cmnplclc remission lute (patients were r*4 jrenl mlrosm iiiinds hut the rigorously restiigcd in either the l.(X)(; ,,t SVL't fieri I he Ion studies liowcvei)111 l (.(K. hits recently c,,m. {lyeloslippressi Iileli 11 ptoliH iils utilizing IK A I' in mie arm aslaith ptake with sh an induction mill maintenance regimen for pat|PI)tl with all histologic sillily |M's ol nmi-l loilgkiii', l\ 111 pi ii mi.is o been postu Nitrosourea' i*eeks in a sing In u slndv ol palieiils with niHliilar patlrrn dial severe hei Ivinphmua ol all histologies and dittuse W'ell-dif, ipon in early lerenM.lied lymphocytic Ivmphornas,1^ R(:vp ffiurpus may c vielded a emnplele res|Xitisc rate ol 50" compared (pettias, tinprei to 52' lm' ( d' mid 5'Vi lor (.VI1 plus procarbazine jnlfative mar tl A TlM One-year iicriintuges ol survival were must lx' uimii 77"i lm IK V 1`, 05'i lor I T and SO'; (or CVpf (l-osoiirea thei suggesting llor liivorahle noli-1 lixlgkin s Ivrnplimnas moderate treatment with eyolophn*. patients deuu sitrosotireas phanitde plus predtnvnie is as elleelive as the more patients pres intensive lonr-drug regiitiens jrul/or radii In unlavorahle difluse histology non-Hodgkin's pulmonary t< Iv inphimias.1 IK A I1 w as i mnpiired to ( ,VP p|,iv potential leu udi mini cm mid to I AT plus Iilemnyem, t)ie *rutms lilcmnvi m Lung given m two dillercnt m hcdules \s single I umipli'le reS|X)iiders were then randomized to n() aCtiv its in H lher.i|)s oi IK A I1 lor I1/; sears Initial results in photna 1 he dicate that the (A I' plus ailriamyein induction arm .ions ill potH provides u higher [x ri (Ullage ol complete remis- prev ioltsly tl simis us well us Imigei mediun rcs|xinsc duralion Their role ri .mil ov n .ill siirv i v ul cm u pa red to the IK AT arm oitihmcd nr .mil one ol the two (.VI1 plus bleomycin arms patients with Tovieitv was more lre<|uent with RCA P than in the RC'.NU-prt nthri three .inns t he maiiiten.iiiee phase of the therapy in i studs is on-going hut no sin \ iv ;il dillerences are as nit*lphalan-[ vet apparent m the group ol complete re greased toxii sponders regimens ir Ration hut Discussion |K Nl . an lirst-line di The iittiosimrcas, IK INI', ('.(.Nl . and ninths I lignant mt (( Nt have u w nlc i.mge ol ucliv its in hiiiiuu ,,|inv alent iii.iligtiiineies Tiles were s\ iilhesi/ed us part ol the mtrosoiire; Vil ion. 11 < uiieei I list it i Me s ill ug M ui a ling program uii|iowi`d ' .mil have Undergone estcnsiie ei.iln.illmi in Isitli m, ellieac .iiiiiii.iI mid hnni.in neoplasms Nitrosoureas mai .vstetn me I < \ \ i u ( ' INK SI I 1.1 SI I'li'l Mt 1 "I.IHI- A till 1 < <k; ' "in. hlMnln. '"lllltla. 1 ' *'li J ' " iiul " si.(; 1 i'iiiiiimiii Patients 'Inkin'* pattern ' `ll-ili(. iu:\ |> "`pared "li.i/inc ll IT|. < \ l>|. " ' l\ m- *<' lunrc ''lupin's ' "plus tilthedlllcs I'll I" 11(1 'ills III' '"ii arm ' t'Itllsbunlion ^ ' Till " .Tins "I Ml the i i il I li<> an- `IS It'll- re- II ii TI is I 1111 M I.! I, II ill ||,,. '"glam III III ill I MS lllas (L I IS multiple 11 It-ll l.l 11 |SI 11 s Tiles base ill" ,,|lls ill III i'll III ail as alks la I nig agents, In r.il ,s la 11` pnilrin In ininliil i me-cai linn iiii'talm . M and I" IM11 -11 mi- \t ll Ii I In- ss lit I ii -sis n| pm 11 it di-nlldes I'h.u iii.ienkindie si 11< I it -s t It'll it >i isl r;it t1 -id Uisliimilt'slInal absorption prolonged plasma ,P ami ceielunspma! Hind |ieiielialinii Tin ,,-lit 111111 isi m 111-a s appi-ai In lie Itiaclisi' ininmills lull 11 in mi 11 s i i in'I al >< 'III's 11-ina i n nindi'ii in! I'll" long duration n! action and di'lascd i'limii|i|irt'ssiiin am micsplaini'd although tissue iljls" ss itli slots relcaM' nl 11 it' aelise ini'lalinlitcs i,, lieen poslulated \itnist>urt-iis mas In* administered esers (i S ...els-S Ml a single-dose schedule It must lie stressed i jt sesere liematnlogu -lelaled Insirils ssas ( uin.,.11 in t'arly clinieal and animal studies \itin.ureas may cause long-duration |ienplieral c>toviiias, iinpredielalile IiIihkI euimt nadirs, and eil- ulaliM' ilia ill 'ss Insults < omplelr lilnnd enuills ilsl 11" mniiilured at least nnec a ss cek dm ulg ui,iu n 11 ea I lieraps and pi el el al ile Its ue a ss eels ill clients demoiisliatmg I mill eal Is autl late itadns silriisuureas are especialls mselosuppressive III jlii'iils preslousls treated ssilli eliemnllieraps al nr ludinlluTaps Heeeiitls deserilied latal iliiinnars lusu ils. elimuie renal lailure. and tlie ..It'litial leukelimgellic el leets need I urtlicr elnse rutiits \s single agents mlinsnnieas liase llieu I test IIS its III Hi It Ink HIS disease and maligna lit Is ill- 'inina Tiles apiiear In aelliese objective relllis- iiis ill patients ss itli reelirrent malignant glioma vsinusls liealed ss itli singers and radii it lieraps lu'ii mle lem.nns In lie delnied as part nl initial . a I d " l led mndalils tlieraps in ness Is diagnosed jlieiits ss itli glioma. BOM'-prednisone initial remission induction ,,raps in mseloma compares favorably with idplialaii prednisone Inti is Irouglit ssilli m- ,rased toxicity The efficacy of BC.'N Id-containing .^linens in refractory myeloma is under investijlnhi lull ap|tears promising The nilrosoureas (Nl and nis'llisl ll \l sail Iv vonsidcicd -I-line drugs in patients ss itli slissemmated m-e snanl melanoma and priHluee res|>onse rates 1 pus - dent to that seen ssilli l)Tll! Surprismgls , iriisnnreas are not additise to D TK'm lei ms "I . ;!|iniseiI res|ioiise rales, and as single agents lias e j .-illuass m the llealmenl nl celill.il neisnus I .stem mctastjscs from melanoma Vn ale.i n| sue.d n,n ,, |I(w,p im ol mi- 11 m i I limn hi: i mill .n tit a lie -e ad |H\ a I it llieiaps in uaslne and i nlnn-i l.,| , allser Ues|Miiisi I ales III pal lent s ss 1111 ad sal III ,1 Ui,s|ni. and i nli i- n i tal e.meei ale nlten mereased , mnpared to single agent .VIInoioin.u ll tlier.ips ll ti.i|n-d that this nliseisalion ran lie lianslaled ml i pn .longed si ll s Is a I III pal ii-nls ss ll h a mi ue limited ilw a - ss hn a I e a I high I Isk nl l e< III I em e Inllnss mg del Mill is n smgeis \l piesenl ntlrnsmirea I Innrmiras ll e< niiliiii.it inn l hi -1 aps should not lie considered slandaid llieiaps ill metastatic gastrointestinal malignant s iieeanse nl the lailure In document miptns ed oil s isal S'ltinsnmeas have their major role as part nl combined mndalils (lieraps in patients swill dis seminated "i adsanccd lncah/ed inahgnaiu u-s In addition, nesser analogs ol the nitrosoureas are I mmg ss nl In-si ml and clinical phase I II trials ss itli ehloin/nlncm base ii-eentls been initialed 1 1 ls I bis i oin|MMind belongs to a class nl mlinsniirea analogs which jsissess glveosidie sld<- groups, ll lias sigmlie.ini .mlilmuoi activity against 1,121(1 leu kemia and produces only a minor degree ol inhi bition nl iimiise and Immati Ihuic marrow l)\A s\ lit I ii'sis eniiijlaled In III !\11 1 'I lie three nitro soureas res ii ssed in ibis pa|ier, |)lns slreplo/ntoein and miss eliloro/nloein. are major additions to the elieiiuitlier,ipisl s arsenal I lojiefully, further studies ssill In-tier ii it-| it 11 s llie optimal role of nitrosoureas ill the treatment ol patients ssilli cancer ( \( K\()\VI.|-:i)( ;mi-:\ I ( .1 .till M|| i| WH I \\ ,|\ | III l\ nil'll III |>.l! t l>\ \.ll lnit.ll Instil I |h \ <>l I tr.iltli t'l.inU < N IMtHi.miM \ I < r>2') 111 Kit I hr Vilnm.il ( .tin ri Inslthilr Urfrriliu*t`s I ( .nU'i S k Si Ii.iIh-I I' \| . lirmlrr, L K . r( jI I > lil(iu`lli\I)-1 -nitiusimit'ii (lUiNl ) ,uid >11 h i nil n im mi r,is in ( am rr tir.il iin-nl ,i irv irv\ \<h ( i,ni i * ii. tf> -r i >;/ /'/rJ 1 * J, ' k I 1 1 1 , . it ! \ I "s J-I l||f -t I *'t 1) s | 1 - Mi tt l W . i .i - 1 i 'j n i i rum i >t fMimr' /V>r \m \ ( nn< ci /<rs f> hj, IttftS >i limilrt I. I .mil ( arti-r.S k I'.im mat ir isirt i rll i .in niiinia I < Innral Ir.ilurrs nl a2 (Mtlrnts \/<m /uh i ti \tul 7l) 1(11 107, 107-1 1 1111 if I* i I I- .imlt .irtrr S k I'anrri-alu lilrt mil mu i n* m i i.t II Krsnltsiil |)iri,t|n u itli \tr<|>ti/nlitrm in .")2 |bit irnls ,\ff ft Intern \lc<i 70 IH, 107-1 il'2 Nitrosoureas K;*t/ (dick 3 ( ,rirlH` M f > .lHll (.|( ruin ^ | | ) |( JI | I V 11 nl III los<'CM.imdm v u* mho ,im ii. s ................. ,, nu) , ( tin f t fit x 20 / H'O I11 2, I'MAt f> Ski|i|M`f, H l1 ^ ImU'I. 1- M lr.iilir M \\ * t al I'ximnnirnhd i \ ,i In. 11 lot i <>! {h>Ii i in,t! ,miu ,itnn acrnls \ I \ii,il<uitH distillml mu itjk mi.i i c lls and l.nlmc "1 i In mimIIu iapx ( it hi i i /{i \ 2/ lOiil 7 St liaUi I M JniihstitM I 1' Mil nltli (. S t I ,J I \|k i imi nl.il i valuation nl {HiUnti.ii .intii.imri audits \ III I'llnls mI tritaHi ml M im mi I * '.Is i'll Kill .H'ri rl n a I I I2IH Ii nki mi.i ( fimci /{< x J.> 723-733 m.; S SrliaU'l I* M In \ iv i* Irnkruna i ll kill Liiu I k'\ and i hi .il ulil \ m r\|H'i niu nUil a `'Umiiv In / fir /Vo- hjvr<Uun\ <m</ .Sprrud o) Seoplastn Cells. TuentijFirst \nnuuf Symposium on Fundamental Cancer Hcseftrih, IM>7 Tin* l hiwimIv o| IrsaxM I) \11drtsnn Hospital ami Tunint Institute at I Innslnn \\ illi.mis .uni W likin'* Rallnimrc. I*KiT pp IT1) 40h (1 \kiMi. j (i I .aster. M R. Andrews. ( M , cl al Sneers* and lailurr in tin* treatment of solid tumors 111 ( uie ' nl mrlastatie I ,rx\ is lung t iiruintna w illi mrtlix I t < SI i\S< `Dill' alul *HlitrU t lientn ||m'j.j|\ < mu i i ( In nu>tIn i H* p ( A i (0 /V72 l(> Wini li t (, I' lkiwdniiR J \damsou, l) ) rt a! I Herts nl | -1 mi 2`eldtMnet lx I1 nit rosm it ra and Millli' cllrtnli all' I rlaird t nil! j mi mils M|*imi dll' I III I girssionnl i iiIIiimm! 11 I'p So 2 rrlU through the Cell i \ rii` (dm it iu s >o /m: /s_?r nm 11 St tilil.dl H ( lirllg D I FilliUUUUa S rial Mini itlealion i| pmtrms l\ I 2 t lili in ml Ii\ t > < u ln hr\\ I -1 - ml him ultra > SS( T4H >* >T > v\ itli mu Iru acids and proteins ui \ dm OuirerRtx >2 22-27. I Mi 2 12 (ham* (' ] Puiuinna S (irMiilx'rvli'r. 1) , ft al I (ill Tart it'll nl I -liZ-rldnrtH'tliS I '-Vrs t lolirw ! I mi II i'maura * \Sl T'Ml, iT 1 u it 11 nm Irir n ids ,md |*i n inns in mu .mil in \ 111n (anti) lU \ \2 22 2. I'>72 I i W lirrlri t> I' and lUiwdni K | lllrtlsnl I ^ I Ms 1 J rlil"|m I liv 11 i ml It isi Mil i`a H|*'li l In s\ lit In Ms ui jMntrin and nm Iru arids in \i\n anti in \ilin i r Mrs J.y 1770-177S. lOtt.s II W lirrlrr ( l` and I Immlrv S \lk\luhmi at ti\i!\ nl I VIms-i 2-i li|i iinrtln 1--1'lilt rtsniirra ami n latrd iini[)nunds j Ucd Chctu 10 2M, MjIiT l>, Jriwn |) I'.andHrtd l) J |)nrt t r\klrmr (nr ])\ A plkisplrntrirstri Inrmalmn In inlinsmirr n Vu* \/M S(M ( /mi < tm nl is 72 nr: Ml ( ,alt < . II I I It . I nl I l las i 2 > lil'ini tin I' I m trnsninra im l lnluli asiUrs luiiH'i 'lls Him lu ni Fhurnutrol It 170^-1710 1077 IT \\ lirrlrr (> I* .mil llmnlmi H | : 1 11 n I x 11| I * I Us. 2 i lll'M i h 111 \ I I I nil I Mxri n ra and 11 la! d i Mu j mi ii iiN ihmii I lie s\ ntlu-stv ui iilllni s\s l ins ( mu i ) firs JS *2 V/ /'/nS I s slut ak iu S i in I I n t l tauj> u il im . ll i r l 1 In a nl It 'll in a arrnt s "> ulnm 1 Ii v h t u/i in -unit la/nli In ai I'vaimdr and I > In si 2-t lilt hi mi ii \ I ' I mtmsi m 111 i mm ii II i ti It'ni I I 2 MI It n In n m < lls 111 \ n i , r,, x m 2t71 2i:o torn |f) l.n.tl, I) V \) w. 1m J M \nulrt W Rifit4i Srlri 11 m ` miiI.iIm iIk t lirtlvnl I Vlas; -i'chloroethd. I mtrnsi>uira n|mn dr nnvn pnrinr bimvnlivMfc f mu cr i\< \ II l>2- (fj, 1071 2U <lli\run ^ 1 limit.kii;\ iiid pliannat nln^s i4 t) intinsiiurras (uii/rr ( hrmtlwr Hrp /.'j.jj 107 i 21 | )r\ 11.i \ I Drliliain ( |).ivuls<iu J H . el g| 7)^ |ili\sinlunual disjxiMUun i*| die tjrnnosUiic j ^ I mm 2-i liInn mdiv I ;* 1 -nilrnsrnrrd (ll( A l 1 in nian nd annuals ( Im I'lunnntcul I'hvrS W>o77. J,%7 22 S|>nii/n H W OrA it.i \ I , and Oliwrm, 7 I'li\ mii|tit'll dis|Misilfnn nl M'2-< Idnrnethsl]^ 4. mrliivl ( \< Inlwvs IM -nilrnsnurru i\tr< X !\k ; ,n^ UH-tVM, 1072 2\ Oltxrrm. V T , Virt/kr W M , S\riUiams, \1 ^ ^ al l*lir alixorplmn, tlixlnlmlinn, rxcrelion and Uo translnrinatKiti nj Uu* carcuuvsUMc l-(2*chfc^ r(K*l!i\l)-.`A^vtlol>ex\l'l*mtro5ourea in anim*k Cnju'er Hrs 20- 133iri337. 1970. 24 Hra\. 1) , Olivenn. A . Adamson, R . pt al Cfllc\<^ rllrt ts prndiirrd li\ I -(2*i'li)nroi`lhvi)-l-cxclol^. \l I mtinsmirra <.( ( Sl l and its dmimpow*^ jnmlnt is /'mi \111 \'st ( nnt'i'r Hcs 11 /2,/9*o 2"j lam, I I , l)mn, K L . Oixnu. U L,,,etal Thpjnh tumor l,^d5i2schloropth\!)-l-nitrosoiirfi, * Hlutrm St i 33: J92--I97. 2<` W.issriinau T 11 llir mtinsnniras \n niitluie <4 t limral M-lirtlulr and Inv ir ri lot Is ( tint rr 7`rrui flll( t,0 700 711. 1070 ^ '27 Mimitrl < (* 'Hirrapx ni ad\an< rtl i'astruin|,.>jMg| i alit n w it f t llir mirnsnuiras ( ,um rr ( Iwmolhi'r Hn* i 27 i/, /`/ri 1H Aoiing, R (] Walker, \1 D , Canct llos, C P et Initial clinical trials with methvl (f]\[ (iMi i Rlnrnrtln 4-mrths I r\( Inlirxv I'-1 -mtrnsonrc4 ( mu rr il 1101 110U (07 > 2M I >r\ ila \ 1' ( arlmm I' I' andtKvrtis \ (] ^ al ( linn a I 11 tals x\ itli i x lns\ 2 t liloMmllo } i. j ll( I tost mo a \St , Ht4><)2 i mu rr Hr\ 2% IH7fi-l\.\i 101 <3 >0 lassiirr, 11 V. R( SI, ll ddiix^HliIofitHhUM mtrnsniirra) I' llrt ts ofi adx atu rd 1 Intlgkm s and nllirr nrnplaxia O/urrr 22 lo/ l5f, /%A >1 Srlmri r \ p , ()krn M M anti Jolinsnu. (i j (,v nr( noMsha x\ ith mlrosnurra tlicrapx ( nnrcr Treat Hep H2 571-57/). I97h i2 Durattl J H S'orgartl M j Murad T SI r| j| I'ldinnti.ti s ttsu it\ assuriatrd xx illi lust lilnrnri|,v| mt i nsi mn ,i {IU St ) \n it I ii f i i ii Mill Off /'/D/M nm v> Molo\c I* A Jrnkim I) K , and (ircvnlnTg s t) l*ti!mnnar\ losuih in Inng-trim aduunistr.itiDn ,,| li< \l l tun it / tin/ /ii phO }00} lhO{ 107ft il Halit v ( ( Maisdrtt (( H , and MornsJum v | |j 1'ild pitlmnnaiv Id mums Inllnxx ini' ! > Iasi 2 < !,),,, milivli I ml i mm inir.i i IU St illiriapv ('/o<< <t | > 71 70. 107S m S Ikrr R (1 jarnlis S \ aodMonrr I* lntiisim.,1 pidnmn r i I il M nvis as a i "inpln ,tt n >n ' <1 I i lilv J r W \\ . rt *1 ^mj^-ihWnethylF * ir himvnlhet* li.ii m.Kolo^v <4 the . tin* t n 20. v.>n J I), <*t A TV* > .m.inD-jlaiii' W iU \l i in m;ih *tid 744-771, i%t ml (>hverm V T ` i hh>rnethv t < "V \ 4 Mc<'( SI ' in nun W ilium*. M K . *t aireturn and bk 'static 1-a-thio- rru m inim*k U i*l A CellcycW eth\B-'Vc\clohev its <Uvnm\MH.\t>ori n.*x /1 j,,\ i rial Thfanu- %(-1-iutn>vmrra / i as \n outline <<( ( dm < i I r* nf p '! 0'lr<Miili,|llu| 'ln iilnlhrrllr . (. 1' .-I jt t\ ( < ( S', , |.,J v I * 1-mtTuvmrra - i t \ \\ et hh>nv\Ini' I ni . v J > /\74 ISM J hlnruethv l \ \ l<Kl-^Lm v * I -1 P>4S .tltimui (. J (,v iv I uni cr Trent i it! I M ft al l I ii*c Iil<*l11\ | .1. <i '*<) tot tot <u fulieri* S I) nhmmstratu>u <i| / toot. io:o I. 'i > n l* 'UiF n t l I..VM!!, | >\ < < m i r (2 .it I* luleMiUat lllll '( | \ luv. ' (amjh (7 ink M liuai.s Winter. 1979 717 chlornelhvh-l-iiitrusnniea (IK M ) thrrapv I'kk \nt \sux f7m Oncol 19 777, /`/7S Willson, J k V I'ulmoiMi v lovii il v ol .ihliuri ipl.nt h drill's Cancer Treat Ite/i 62, 200-1 200S. tiiTS llt-llot. I* A , and Vaidiserri It () M*iIt (di- ixiIimm naiv lesions m .i palunl ticalcd with IK \l I , Insi2-i hlororlhvl)-1 .introsonn-.i) for I'liobl.ishuri.i mulldnrme (lamer M Ift 79, 1979 !.<<, W Moure || P .tncf Wainplel (- I. Illlrr n|I l.il J mliih Hi:ii \ | iIh< >si> .is .i i nf ii|iIh ;i( i<n < *1 j >i< i Inni'tsI mediv I <.( \l 'thrrapv (umet t rent tU pi>2 I >.55- I75.S 1974, Jensen-Aknla. M lte|nrt on renal ahnnHnaliliesas wialcd with prolonged infllnl ( CM ihetapv \ lrn Htf and mil lioni I )rpl d I leallh I',dm a In >n, .md Wcllure National Institute^ n| Health, Fehruarv I SiTt-I Ihnnum. \\ l, , < 'iilw n. H j , S hm'`ln*u;fi. I*. |-, i t .i I ( 111 * m iff icn.d I .t 11 in < - in i Inldii ii 11 < ',i 11 *11 with niftln I ('CM1 A' /.*>: J Metl 1200-t'Mt SiIvit. II K li. and Mortnii. I) I. ( X !\l nrphrotovKitN lollnwsn.slaiiifd rfimssiim mi nal ft-il tarfiiMuna Camrr Trvut Repli`1: 22(>~'227. W79 (,nhfn It J, UitTiid. P II and Waller M I) \i'Mlf IliUlK |||||||4H \ ||f If llli'llll.l .*SSi n filed w it 11 III trnsonreu filenmlhfrap\ A r<`|Xirt ul two e.iws Cdiwer Treat Rep 00. I2l7-I2tot. I97<j W.isM-rindii, T H Sl.ivik. M .md (l.irliT S K Iti*\ iew ill (!(`M in t Itnif.il e.inert' lliei.ip\ ( 'inn er Trent Per l Id MM PJ7 I W.issernun. T II . Sl.ml, M . .md ('arltT, S k Mrllnl (X!\l in ilum.d eaneer tluraps Cnmrr Trent Ret I 2$i 2f>9. IT/ \|ierli-| < Si hull \ j llctlt-mni i It ] i-t ,il I I it`raps lir t;as|i4Mii(f\|in.d i a heel w ilh the inliii- sotirras jlntir jnd in dru^ ei unlmutinn i 'uneer Trent Rep 00 729-7.12, I97(i \|intIel (, (`linteal m.inat'einrtil <>1 ad\iin<ed U.isiminli'slinal < aneei ('urn et .'#* I>77 I>SJ, Itl77t ( .irtiT, S k InleCratimi nl elienmther.ips inti* ininluiM'd rmkLilit\ (n altnenl i?t snlnl luimiis \ || \dem h art tniiina nl I he I >ieasl ( utn er Trent Ret I 111 171 I97R ( on ns, It L DTK11 \S(' in malignant tnrl- annina \ prov|H`etne Ofinrr Treat Rep R0: Uii- 17h 197ft Wassrrnun T II, Slavik, M. and (!ailiki S k ( linieul itimpansoti nl (!< mlrnMHireu-. C nnter U) f-WS-I2^S. 1977. (ailtlsinilh, \1 \ and < ailei S k (dnthl.isluni i multiltHClW' a if s ww *>1 thei aps ( mu i i 1 n <it hi i I M7I Morrtfl, C. Ci. Natural histnr* t>t ^astmintrstinal cancer In Advanced Gastrointestinal C.oncer, ('hnti nl Mutut^enu'tit mul ( hemnthcrupu, ( Mi N't U-I ant I It j Itrilfitfin I-1 Is I lal | >el .md Itt iv\ \ew 'ta l PHt'l pp l || MtN'ilcl t (. ( liemtithriapv '>1 u.nliMUileslnial tain ft ( tin t'.u\tnu nteml 7 777 7l/. I97t> ki\a<li | S MtH'ilfl ( (. Vhlilt, \ j et al \ t <>nl11died s\ud\ nl finnlnnrd and 7-flute rnuraetl llietapv hif advatieed li-istrie and [ijnereatK tamer (uturr M 7li I 767. (97 i \hn rlel < (. . Miltelniaii, J \ Itakrmrier. It I', el ai Sfipif nl>al and < nitdnnation c hemuthefapv nf advaim-d ^aslrn tamer (.timer 1H h7H-(tH2. 1979 Min-lit I ( I- .iml l.avin, I* T An evalnatinn nf 7-11 , nilrttsoure.i and laelntie enmhmatinns m llie 11 i-t .111 \ nl 11 p| tf ( ua^htiHilesiinal cant nr I'roi Am Sf/f' ( /in ( hu nt IV i 11 1977 ()( uimell, M J . Mnrrtel. (' (i , and Lavin. P T \dnamvi in. 7-1 hiinnor.H tl phi'' rnitnihvein (l plus t \ tnsiiie aialiinnside. and Adliinmnrac il, adnatnw'iii plus nielli v I ( i !\l1 in ads at iced gust fie caretnnma /Six \u Six (.7m Onenf 19. 747, J97^. Mitertel.ti (^ , O ( amnrll, M j . and Lavin. P T < hemttlhfiaps nl ^aslru eiireinnnia. l'riM` Ant Assoc ( nmn Res 20. 2SS, 1979 linrnkt r, T , kiin. P. N , Mnlbrun, N . rl ai 5-F\J tniiiMnn with iintnniycin (' vs 5-FT infusmn with iiH thsI (!CNL: in the treatment of upper gastroin testinal eanerr A |)hase III studv. Proc AmSoeCtm (hteol 19 7/0, W7H I .iiHsirmn. P F , ( jitalanti. It It, and f'reech, R W , Pliasf 11 si nd\ n| met h\ I ( !(]\t1 (NS( ! !I7 111 ) in ad- vaiK-rrl ^.istmnitestiiial t umvr Cancer Treat Rep 00: 24.5-2*7, 1976' (.edrrrnark, B J . Dulolkar. M. S . and Elias, E G Met In t i X ;Nl! {NS(! i)5111) in advanced cidnrectal v airmenta alter failure <f Vlluoronracil (NSC 19SW) therapv (*rurr Treat Rep 60- 235-23H* 1976. M' Dnmdass, It O,. and MiHTtel, C Chemotherapy of |)revnMisl\ trslml <`o|orn`tal adeiMKarcinomas with int-lhvl ( CM nr U`ta-2'<h*nxvthio^uanmim` (inct)lti .iplusell III s(nd\ t>1 (:<:(X; Ton ,-tm Sue ('tin Omul tT'.iOd. 197ft l2 Douulass, II. <),, latvm, P T . Moertel, (l G , et al ( w ltiphnsphamide nr (vlhini'iiamm* plus 7-fln<>mni.n d vs iiiflhv I < '( !\l1 in 7-lhinrnnraeil alone in (he In atnirnl nl advaiK-ed c'oloreetul carc inoma An rasU'in (`nopTahve ()ncoloC> (rnup (F(XX-) studv Tim \m \vvm ('nmer Res IS 177, /977 Miierlrl, C C , Seluill, A J , Hahn. H C ,, et ai rh< ra|>> nl advanced colorectal cancer with a combmatum of 5-flvtorouraiii, methyl-1,7-bis (2-chlnrnetIn 1 }* I -nitrosourea and vincristine J Satt Cancer hist 74 49-7/, 1977 l alksitn (; and FalkstHi, II (i Fluorouracil. methvl < A ,M and vincristine in cancer of tlie colon Cancer IS / MS-1 170. 1976 It.iki'i I. II lalh v It VS M.ilh i It . el al Ph.isi' III uiinp.iiiMiti nl llii1 tieahneiii nl .ulvaneed ^.istrnmlevliiial cancer with Ixilus wet*kly 7-FU vs methvl <'C\L plus Mus weekK 5-FU Cancer 74. 1-7 197ft MaiDmi.dd | S keMii i D F Smvllir, T i-t al 7 I liinmiM.M tl inethv I ( t \l ami vmensline in llie (icatmiiv^ nl advameil fiilmi'etal cancer Phase II sludv usmv* wieklv 7 I t Cunter Treat Rep 00 I 597 ItiOO, 1970 I n^sltiun. P . M.ulnlvre, J , IXmi^Ijss. II et al ay r 314 Nitrosoureas / Kut/. ('dirk < OMlillliallOt) IM M M it l M `t .11 V n| |iK.||ii lm\N<l (aiKcr l}r(H Km Six ( lutihnr/l 10 i\ I fo7\ ftS Mnertel. (] (i, O'Xamnell, M J UitK II Fetal A controlled evaluation ot con tinned unnninotherapv (MKH-IU ( i) and ehemothrrapv I*r ad vatu rd < olorectul cuiuvr In hnmtmnlhrrafni oj ( amrr Present Status of Truth in Man. W l) Tern ,iu<l 1) Win dhorst. I'd** Raven Press, New 5ork I97H, pp 57 J r>Hh 09 Rurnker, T Kim. I* \ , (Jropjjc, . ft at , o-Kl mlusion with nntomvein ( vs 5-Fl infusion with inelliv I ( X At ill Ilif trfatnu iil i>i .niv.iiierd rolou cancer Camt`r/2 122S-1255. I07S 70 Delicti, j J , Skurin. A, T , Maver, R J . ft al Lack of effectiveness of comhuu*d 5'fhiorottr.kcil ami methv I ( X Al iherapv in advanced colon via I ran (i*r Cattfrr ttt 2702-2700. 1077 71 List ln-0i. M It Carrs, H W Wril/inan.S A il.it Treatment ot advjiind colorectal canter with a (omhmjtmn ol 5-f luorouracit and mrtlivl (X.'Nl Med Peduttr < >n<*fd J; 277-27H. 1H7H 72 kaue. R (7, (ladidotlar, M, \\ . and IVrnath, A M Treatment of udvanml eolorivtal cancer with mrthvl < ( NL plus * <l:i\ 5 flncMiurafii inlusion ('aturr l tent iU j* 02. 1521 1525 tUTfi 7 1 krtncnv. N . Yugodu. A , llruun. l), ft al A ran domized s(mi\ of two different scludiilcs of inethv I l X A l . 5-R1 ami vincristine for mctuslatu color* vt.l uiin'r (muer Vi 7S-S2. 1070 71 krnicnv. \ Tigoda, A, and (iolliev, It \lrlli\l (XAl1. Adhiorouracil. vincristine and slrfptn/olnrin tMOF-STRKP) for metastatic colorectal rarrinotna /Vof \ni Kwtte Cftti Oncot flf 515. MTS 75 Cirrfo I1' \ l<it hardson, It I. . S< linlmaii. S I* , rt at (JMiibiiiatioo of constant infusion 3-llnorourafil, methv l (X A l . mitomycin (' and vincristine in ad vanc'd folori'vtal carcinoma (7/mrr 7 real Pep 02 1107 IMS. IU7S 70 Sliaw .M I , and t Ifillirun, I. K Rakei s anlilot in i oml `ihalum vv ith methv I ( X Al1 and At htnrum aed loi (lif lieahm-tit oi liiflaslalif ii`tooi t.il caluvr /'rr* \ in St* ( Im t him! 211 tnn, 77 iVm . M C , \\ hitr, l. , and kardinal t 5-ltno loniaiil nifllivl < ( \l and dannoimttn in ad valu'd i'olorivtal adfUm-arcmonia l'r<k Km Vjc (/in < >m'o/ O-S. 79 7S lokultj J \vljiuaut UuTapv lor Mr\;uallv unatilf colon cancer; A controlled studv ol clictno and imnmne thcrapv. Proc Am Sot ( tm Onto! 2d 12 i W7ff. <9 |)a\ is, i I I. , and kiMif r I) I, \iulv sis nl .utiov.ml tlicrapv in latuc Ixivvrl caiu it (Hiurrilui Imfh I 27:i-'2S7t J97A Ml Stcplu'iis. K l., Hoo^stratrn. Minis, f', rt at I'anrrcatif iailffr trcatMl with rarinnshnr tlno loni.ifil and spitniiolarlonr \i< It lnlt'Ht \/< tl I J-S M5 U7. I97S Hi lielid, It l, MastraiiMvIii, M 1 Ik-rd. t), ft .d Mflaiioma flu'tnotluTapv In (ViMrer ('ht titolhrmpif 1U. \ Ilrodskv and S It kahn, Kits (.nmr and Stratton. New York tn press H2 t ,t r I > >iif J* I' uni ( osn I to \\ I aslrrn ( >{ t <hw t.ouip Stidu`s with t ) I It i \Sl , i.WSS i / n at lit )> HO 1*1 I PIS. Id7h vl Natliansnn I,. ( mniiiij*harn, T . KufX'rnmu \f .d t oinhinatioij fh* niomiinutiotlirrjp\ of malignafi nii lauonu Prtu \in Sof ( 71n (tin of 20 )/j HI Mikflvi-v, l` M lain1 j k , I'.dlov, U \\ 4| < omliin.ition i liftnodifrupv w itli lt( ,Nl. urunvir^ and tVriC in dissrnnnatd inaliunant mi'lynofru 1 umrr.id ) l idJ7 S5 Mfkfivfy, K M , laicc, J K . Vaitkevunis, V k al IK At , v iru ristitif, DTK! urn! chlnrpromarif* fomlvinatmti fhfinotlifrapv in diva*imiia(n) main nanl ntflanoma i'anwr^H 5-10. Id77, SH (aw(an/i. J J ( difmothcnipy and iKXi in tlic tr^p incut of dissfminatfd melanoma A Soutlmrst ()*. (irnup Studv f'rof Am So< (,/jf, Ofl(0/ o ///, NTT S7 < oslaii/i. J J \I-Sanaf M . |)uon, I) () ( hrmoniwnunuihrrapv hr disM'initiatcd m^l*. noma- jS\V(Kistu<lv Poh- .\m Site Clin Oncol20502. NTH. SM I "oMan/i J J , Vaitkfvictui. V, K . Qnagluna, J M ft al ( omhntuiion t. hrmothcrapv for disscnnrutrd nialii*ii.int nifianoma Ctnitrr 15 Muss, II II . VVliitr, l> ft . Mu liaids, K ( ft j(, atovcm and (X'.Nl5 in the truatmiMit of advinct^ hn-ast miifit Cf/nrrr Trent Mep fiO 10H7^ 1070 ^ all. II W.Saiki, J ll/rramun. H I -, t-t at. Adn.uuwiu and (X!NK m advancini hn-asl cancer ( ant rr ( lin 7>ir//v TH~lL IH?H l)l W alrriifld, \\ (' , Tudiima. ( k , llortohagvi C \ , <*i al \driainvcih and C (At in the trcainicnt ol iiirtastatu turasl rauccr (.iniirr U. J2.J.5-J2.& IH7S 92 Tonnev. D t' Adriamvem (NS<' 123127) in hn-ay v am iT \n ovrrviiwv of studies CVinrcr lit ft fi .i/p i27. 1075 'li I'lrxant t, \ kolliousf, J I* . and klahr. (! \dnaitiu in. I i-his(2 fhloro<`tli\I) * I * tMlrosoiirfa (IK \t \S< (O^i K>21 and i VftopliiTspfiainidr m trII at loi v at if iitK aitiuoin.i n| thf hirast and utlvor tumiois ( attit r 17 h2d-t}2S1 1070 `it Itoitoii H Mitfhfh. M FarluT L, ct at (.nmhtnat ion \ ^ fonilnution-sc<tucntul uonhorrfional i lirmothfrapv in advanml hreast cancer FrocAn\ Cam t'r Rc\ 17:2-17. 1070 ')> l.losd, K F Salmon. S K , Join's, S F, ct a I Ran domized trial of low-dose adriamvem and cvclopliospliamidf plus t alnsterone for advanced hreait t an* t /Ho# \m \va/*' ( am rr M<"s 17 120. 1070 'M \flfians \tlunnisiration (am^Caoup Ihostatistic'ians' Mf|xirt prepared for the 47th Meeting of V,\LC Denver, (Colorado May 19-20. 1977 97 lilmonstin. J M , l.agakos, S Sto|l>aeh, I,, ot al Mi ( lilnu lltamoif i \N< ] 7t>2) pins (X.Nl (\SC 790 >71 in tie.itmriit ol mojirrahle stpianums and laige eel) i ait mo....... . the hmg Catitt'f Treat Rep fid <>25-t)27. 1070 9S tulmonson, J H , Lagaktw, S. W . Sclawrv, O S ,et a I (\ elophos|)hamide and (X AT in the treatment "I itiopi i d>if s11*.dl fit t ,tri moina jhd adenor ar(|. (,ree Uadi sllldl ( 0k ( 100 Man.1 t !orrt cer 101 Fres One \ v\t 1()2 Ores tern 1 Id iv a Met 103 S.uii (It in vine van' 106 |04 Cha M\ plu Cat 15 l-IV al--. (NS (NS etK. ear. mo |(H> Me Co of I fit: 107 Wi lilt I OH latin Ire 109 la-v ajiet no Wtl fniii. trea >1 111 Ho al 70 19 112 la B< eii 1,2 113 .V vf vi 111 If OLI 7167 \\( i ii Ci im< \l 'I'm Ms Winter, 1979 315 ss' (`murr "M * *" "sihgiiaiit > */i r W r| ,| ' "u n^liiir "'launuu V K ,rt ,rl>r"<iu?in^ Ill 1 lir trent. "llmi -l <),,. '< < >'iinl is ' " -1 al "",l "i"la- `' H< I`>71 11 'I Adr,. 11 "I'iiiHnl '.`I \dnUllHT '"mum <; 'UlMenl 0-/219, mi bre4st ( hcmothrr " < Xilri. mtrusourea ininle mi re*a lln-r tn. r l>rnc \r>, .`1 Ran**< v/\ r|n- -d hrt`aq '2t> /wrh "lahsl,, ,4lt|V "I ' \l.(f 1 1 . i`t al M t\S< annuls ,m<j f / r< <it /if;i M <> S . *' l rrutinent HleinKtiri.,. huiii.t o| I In lungs < >iu< i t I lift/ /{i/f I<fi < 'I Ilt7l t i>l ( Ireei 11 It 11 x S*-\<U'l II ( Miel h iw skt W e| ,d H,i<li.ilHhi iherapv and c hemntheiapv "I lot ali/i d small t el! earemoma <>t ihe Imig I'rtM \m s(,, ( Ini oiuni jo m, 1*17*1 ,H Hansen |l II, Selawiv O S Simuii II r ,tl ( nmlniMtHHi i hemnthmapv i>l .tiKaiirrd hinc t an m ( ,W4 i t :i.S 220/ 221*7 1**711 ,ll Rresaiit, ( , \ , k lain < Olandci J lei u in H [ilits |U N l m , dv am ed mi \sm ( nin rr Hi s 17 7 1<I77 i I'tesalil ( \ K Lilil ( and S.ml. tein m It mdnetmn nl selisil iv ll V \lll|)ll<l I i-1 MM 2m him net hv 11 1 nihnsnmea eveluphusphainide in human nenpla Mi tl Sh 17 *)/, 1*177 ^ at S.tmsnn M k Haiti 1 II Ini II I 'I .d i ( muimialum i hemnthei apv w ill) t vi >h< ivpli.iiutdi vnuiislme melhv! (.( \l and hleumveMi Mi ad valued I M < Mil ||< tgr IlH t.nemoma |`,\Jiei M`tU e WltFl l(M> patients ( um rr I'rrnl Hi p l>I VI h I. /V, , I ihahmiati \ R Mandel I Holland J I1 . el al M \( ( i Mellmlievale adiiantv<m iveluphns phamidr ,ind ( ( Nl i m ,idv,lined lung eaneei C //ini r /.{ tVMl IVIT. I,I7,I U) lavmgslnu II II l.mliotn I, II Murgess SI V , et al < (iinliiiiatiiui ehemnlherapv vvilli blooms rm !NS(! l2")0t>Ki ,idnamv<in tNN(, I2`)l27t (X Nl i NSt ` ?lMl|T ' v itn list MM1 i NSt l7VT H and uireblm i*l Iunnhr 1 NSt 7l>2 i R \t (>N 1 in m|M;MMiUs i ell lung c.iiKor ! willi Ntl patients Citwer Che- moiln r Hep H >(i/->(r. Ill7> iX) \le\ander M.tdalstem I' J.timdnn I) S rial ( nmbmed iimdabtv tberapv Ini nai eel! earemoma nl the lung \ ia ud<MM/e<I Inal ( inner Treut Hep HI- l-Ik 1D77 :uT Walker | D N it rnsoureas in n ntral Merv nils s\ \teMl Iniimiv ( t/m er ( liinmlhei Iu ji I 21 20 1*17 1 ilS l.evm \ \ and \\ ilsun ( II N it rnsmirea v hemu theiapv Ini pmiiaiv maiiUnaiK uiinmav Cmn'i i l init tlep Ml 7hi 721 hiTH (W l.evtn \ \ and Wilvin ( II < Iieinndieia|n lli agents mi i mi rent iim Sennu Unrul 2 h i h7 1*17^ ,|M lUnit I II HnlJrrv |- U anti l-tmL k J I I- liv 2-t lilnrnellu I n I - nilrnstMirea t \S<! m dm treatmvttl nl brain tnmnrN ( nm cr ( In tni/tln r Hcji -51 27:l-2HI. WTO ;|[ KesnnMum, M L . Hcvimlds A l-' .Snutli K \ et al ( ItlnnirlhyK'VcInlx'W l-nilrtrsnitrea i< ( M \S( T1 M> IT > ( Uiuei'T ( In iimihi i /{/ 121 127 hi72 I nin. \ A . Ilnllman, \\ I*' I'imIut T 1 et al IKM -'-ilMnrnMraeil rnnil>Miatinn llieiapv l->r rr< urient malignant luain tnumiv ( mu ri I n ill Hep h2 21171 21171k HI7S Hi 4 , j Nvellaim^i, \ M llmlt\ I) | andWeM ( II llie e| |< i t iv i iies> nl met Iiv I ( ,< \ t j >n ,ti I ia/ine .mtl vineiMllir Ml the iMalinenl <>l mull I adialetl niahu Maul uhuiMiiN hriH \ni Sim < /in (hunt ht >17, HITS III \\ ilkri M Ii \I* vander !' limit W I*, L et :11 I vain ilmn "I R< Nl a/id <n ia<lmtliera| in tin 11< ,ilnieiil i*l anaplastn ulinmas / Si'iirinttrn ll) i; i u hits \ I ~i \\,dkei M I) au( Slnke T \ \n evalnalmn nf metlivl (I M and iadmtliera|iv in (lie tiealiiinl **l maliv;ii.nil ^Imma I'nu \m \smm < mnn Hi v 17 IH I. h>7h IK* W alk< i M Ii aiidStnke I \ \n intermi analv si*. n| Mint Ii v ||uedlllMilnlle |irt t afl>a/iMe, IU \1 nr HI \ l | ille mt t liv I prednistil* me in tile treatment nf MialiiiMant ulmMi.i I'nu \m \wih ( hui i r He\ 20 21Ml lllT'l I IT Hr.iu.in I I His, I III < inltls I) S . el al < imImlled slntlv nl ( ( Nl aiul ladialinli therapv m malimian! aslMKVlnma J \enro\ur^ II 1SH- hfO, ll)7li I IS St lief n ( I MtHilartlmi, S . HraMilnlla, ( , el al ( i ml milt 11 s| lit I v v\ ll 11 |M N \ s ( (Nt as ad |Mv a nl < iiemnthf iapv Inflnu miu smunrv plus ratlmtfierapv Ini ulinliaslnina nmllilnmie ( nneer ( hn Truth 2I i I.S. 1*17*1 I l*i I Imtnii | , (ilianu, (II, anti Selm4*lel(l, I) ( timhmeil imxlalilv approaches in malignant hr.im uhnma Proi \m \ssim ( inu er Hr\ IS 212. HI77 t J(l I M |t |(1 Hi .im t nnmt (,tttnp, I ffts l nl ( C tin smviv.d rale nl nh)oett\r reimssinii anil ilnralinn nl Iree interval mi patients with malignant brain glioma linal evaluation httr J('nneer HIH.5I-S`.V), /urs 121 Ivans, \ 1 .Jenkm.lt I), I'Ttel. I . et al Adjuvant t liemnthemps ltr Mietlnllnblastnina. interim rejxirt Irniu ( ( ('. fM2 Tror .\m Nor Clin Oncol 2(1. -t25, h47l! 122 Sahnnn, S l` Nitrnsonreas m multiple mvelnma ( tim er 7>c/ Hep HO 7X9-7*11. I*)7h 12 > ( 111m*11, II j \bramsnn, N , Hartolncci, A , et al H< Nl t \t lnphnsphamitle and prinlnisone t IK V) vs melphalaii ami piedmstme (Mid m mvelnma /'me \tn Ntm ( hn (htenl 17 2>S1). IU7H 121 Ueigsagel I) h' , Hailev , \ J . I .atiglev , ( I R , et al I n-almu mI nl pl.eina tell iim eloin.i w itli pietlmsnNe .mil set |iuut nl all t a nal mg nr eont nr rent sehetlnles til melphalan evelophosphamnle and varmnshiie I'rtH \m Sim (7m Onto! IX 129. 1*177 12") ( ase I) ( las- H J , and (llarksnn IV I), Improved sniMval times m multiple mvelnma treateil with melplial.m jiredntsnne v vclnphnsphamnle, vmerislme and R( Nl M-2 prntnenl ,\m ] Mcil f>], X9~*m 1977 IJK \levani.m R Haleer/ak S Maul \ et al Southwest (initilngv (.itinp Iteimssitm niaiiilenaiii e (hetajiv Ini miill iple mvi luma \n h lull rti \ti <i I in II? ri2, h)7~> 127 \IUtIs I) S Dune R (i M , and Salmon, N 1", I )n\t a nl tit m H< Nl t hrmolherapv fur nmltiple imv eluMi.im lelapse I itueel I fljh *)2X. I*)?(i I2S IVamet. | I) \le\anian It , and Salmon S K \ ini 11 si me R( Nt adnaiuM m piislnisime <t mil anal mn lui he.ilmeiil nl nielpli.il.m a I m 1 ev tuxann esistaul mnlhple mvelnin.i I'nu \m Sih ClinOttcoi IX-.142. 1977 m Nitrosowrras ' Katz. (Mirk 1.29 I >0 I >1 I >.! lit IU 111 Mf. I 1. t IS 1 >ll \ndewm I \ I ,ntii\"unc H < IK \t i \St llff M t J l in I In 111 .it nn ill i it n 1 \ 1111 i 11 | | (ti 1 Lin s disca>e Ik iiill hi n 1111'miin iiiilm Iumi ,iiu| mantlcnamr ( am 11 Trial llcp 00 701 707. 1970, Durant, ] 11 H,utol>><(> \ M.nm 11 \ i t .d SoijIIkmsUtII (i.lllirl Stud\ ( . I * t*| I I uU \\ till till I oMMirr.K m I lod\kih % di'seuv ( urn < r /><-/ Hep (\0 7SI 7S7 /To M.i|IK"Ii I) I iimI N< mi.iii r I rimun I umI : i in it i il iliNMiiiiti.iliil Hodt'kin a disease u iili |i< S( alone .Hid in I'Miiiimi.ihiMt uilli wncrislmc |>11h-ir Ita/nic and picdiiisoh'' (iintrr I'rent /Icp 01 7VI 7T 1`lTT Imldsnnlli, M \ .uni ( ailci S K 1 iiinliin.ilinti i lirmntlu r,l>\ "i advamed Ilndt'kiD * disease \ lex n w ( timet ] l I S HO / I l,i k lit uni 11 I ( (P'.tilli* \\ t. Ilnrlnii | .I d 1 I ii 'i i m `i i ii n 111 iii >11 it i.i|i\ it) lludukiti s disease i'iu< \m \wtn ( hn < hu i>l 20 >9J 1979 Durant,) H t.iuih 11 \ \ ele/-Oart ia K , el al !l(\l \elKin i v < L ij )| m iv| it m 1111< It|)l<K'.irlM/llr and ptt'dniMHU' IK \IT> ui adxatned Ilodi'ktns disc.iM- < am i i J/o/ 21 W 197,S i i w f( m * i M K Spun < | ( 1| ii lr \\ i I! <) rt ,d I lie 11} H I H 1||| \ >1 I lllllnsilllll .1 It t \ l 1 < Mill .111 III 11^ 11 Dll dint' i iMiiliin.it mu iivci \l( >1' I * in tin- tiealmenl hI '(.u'r III and I \ I Iml^kin s disease liln/nl (() 101 I. /Ti kutimk | I U ln(i* \( Ware D I cl ,d 111........mm AS< ! 2'itH.tn .mi.I < < \! i\M TOpiT) in l)n i Miii)iiii,lmii 11 hi 11 ) I hi ,i 1m| M< >|'P mmsI.uiI 11<ml\lkiti v diMM^c ( tintrt ('Innmllnt lit ft >9 //c mao. jta t.oldlHall j M .Hid |).m Mill \ \ < < M M111 ll. 11 M MI Mnapx iit ,id\,nurd ic\i\|.int Modukin s disease IninriJ 1221 1227 /Ti \\ illtatii'* S I uilmih I anti Unit 11 < oinlanatinn i licnmiiit r.i|i\ <>| iclt.utoix 1 Ml^km s disease u illi adl i.iiiim in and ( ( \l Hum Vmi Sm (v/iu ( h/ IS 2/>`> l'/77 I.mIi k k (f.iuiIiIc j I SliiiilcttU`r\;ct ( ( ct al 1 Miiilnnatmii lictimlhiT.ipv hi \1<)|,|,-rc,-isl.uil Mtulukin s disnjsr l}r>n \iu StM'Clm Omni IS ]-t2, H/77 Cancer Clin Ti I to I t> i II 1 l'> I !<> i /: l IS I (0 I'l'i/u; k and lit ij h i Km i \ Ticalincnl ill I l< M li' k II | ' < I I S* . | SI \\ (| 11 (1 ( \ \ 1 I I till \\ i uj* \|()jip tailuic I'i/h \tft Sni (JinOiiK/l IS U2, 1^77 la-\i j \ , Wicrmk I* 11 . and Di^s. (` H CfltT1 liinattun tlirinotlu-rapv of advanced pretiotnk Oiatrd iliv.iM1 \m|)i strrplo/n/^tn ( < M adiiamwm amt UnmiU'in Med HvdUllt Omn/.'i 1'1-lfl. JT7 MmsmiI \ l| kill M M tirainc H (, 4| ^ km* tit dU tlcMvincd i liciu>dvi a)H`UKi ii'Hinirn f<4 a<Kai.(`d rclr.u lorv lwn|diorna paOrnK Med Fed ittlrOmnl I Mi- / 19. 197,S l ./dmli |- I'otmk S, llcrafd (. W ct at (im |miimmi mI inlriiMtr \\ iiiixlcralf rlicnmttu`r,4p^ Iv1111*1 m*t \ tit Iwiijiiioina ( Voucr 1<S HXjO- /Tf. Duianl j 11 1 m'li, \ Dorfinaii H cl al il(;\( i \ i`lii|ilnisj>|iainidc \iini|slmc and prcdhisoi^. dl( npi \ new llieia|H'Uln le^mieii lor diltnvc |>IVi l iih ^ tit tv 1111ilmmn.i ( Vimrr Mi Hl'Ht-Hit I, 1,975 l./dmli K (aistcHo \V (/. and Silvtrstcin. \| \ ( licmo|licra|i\ nl pro^novticjlK favorahU llmlvikm^ Utnplinina Mood iS,52` l'/7S (etjusim <> | ( n'Oeliu \\ (l.tVkcn M M .J I In \ dm m| .idi i.niiN < 111 .md ol inid t v < le I rcaliiicTK in niiillMlnu' I lnt a p\ ol 11 id a v im id dc luvlt.lo^v lM)ry I Imlukm s l\niplioin,, l}r(H` \tn AwtH1 Cancer 20 100 1979 /dalla il | Tan ( T f, and >omu; ( iV /`hjy, I I Mat m| i IiImi M/i >li H ill ( `am it 7 n'ttl 10 ft /.'{ 17 i`i:o Motli |) I India T.Winokiir S . et al I'lia^1 l| Mndv ol t lildio/iitncm VrtK \rn \vwm ('hit Omni 19 HITS S< liein I' S , 1`aiiasa, I. WiniIIcn I* \ cl ^1 ||,Jr tuatoloi'v of t Idoio/ottK m anew mlroMMirca jni|, tnnmram tit ( um cr Trail Ih ji 00 S01-H0S, I97ft Adri; 5-flu for at aden treat \|, Anne Kess: John F, Foley Henry M Ler TWIMY^INK 1 .ircnionid pre iiinilmiution nl .ill attempt to p nas observed:: i.jse for a med mitiiinyem C Ii ,n {utieiits will it Ii .J-Fl! M n/e jor leptniK fo Julm II (.lie!.. \tl) ItivspiVui nl llie l iiivri.ili nl IN'iinwIunu, I leniut<ilo^\ Oneiilnyi Set lien iltto Spmte Street, PhiludelpliiH. I'ennsil\J[Uj I `HIM prom the Div Sledictne, L'm Nebraska