907
`Functional folate status as a pmgnostic indicator of toxicity .in
`c!lnlcal trials of the multitargeted antifolate I. Y23H314. Peter H ..
`Zervos', Robert H. Ailed', Dona/dE. Thornton';' and Patricia A. Thiem'.
`'Eli Lilly and Co., Indianapolis, IN., 'University of Colorado, Health
`Scienr..es Center, Dept. of Biochemistry. Biophysics and Genetics.
`Denver, CO.
`S.tudies in. animal models and humans have revealed that folate
`nutritional status may be correlated with toxicity and antitumor activity of
`antifolates. Supplemental folic acid may play a role in protecting against
`Jhe
`toxicities associated with .anlifofate drugs, LY23i514
`is a
`multi-targeted antifolate that inhibits Thymidylate,.synthase, Dihydro(cid:173)
`fo!ate reductas.e and Glycinamide ribonucleotide formyttrans!erase.
`Functional
`folate status, based on serum concentrations of
`homocysteine (HCYS), cystathione.(CYSTAT/; and meth}rlmalonic acid
`(MMA), was assessed in i 16 patients participating in Phase 2 studies of
`LY231514. This drug was administered as a 10-minute infusion once
`every 2l days. Samples were taken prior to initiation of· therapy am!
`prior to .the start of each cycle. CTC tmdcity scores (hematologic and
`non-hematologic}.were assigned at !he end of Bach cycfe. of therap~r
`Eight pts were found .to be folate deficient (elevated l:iCYS. anct
`CYST AT and normal MMA}. Allexperienced ere grade.3 or 4 toxicity
`whloh was primarily hematologic. From this .data, we would concfUdi>:
`that functional lot ate staius appears to be. a. reliable: prognostic indicator
`of hematologic .toxicity that may be experienced from treatment with
`LY231&14. Fu~herinvestigation is warrant.ed to support this conch.Jsion.
`
`GASTR()INTESTfNAL CANCER
`· Gastt(.lnintestl~ai c~o~er . . . ·.
`. ..
`Posterpiscussion SessiOn, Sunday; May 18, 1B97
`
`•soa
`~pll!ncter. sparing: treatment. for di~al rect<tl adljlrici~#cinoma: a
`phase II Intergroup study. £3QJ!..trz~; · JE Herndon, AKtl. Burge!Js', .R.
`Bled<W/r Al-l Russeff, AB Bens6(f\. MA 1-luss.afn', AJ Mayer. 'Canqer
`<J.ildt~Ukeir}ia Group B (CALGB);"Radiation Therapy Oricology Group
`(ATOG);. }Eastern. Cooperative onc6Iogy Group {ECodJ; •southwest
`OncofogyGroup (SWOG).
`.
`.
`Uncontrolled series from single institutions have suggested that the. anal
`sphincter can be presetved in patients (pts) with.superliciaLdistal rectal
`adenqcarcinoma.s {ORA) bot this concept has not been v~lldated)(l a
`fTIUltlinstltutional setting. CALGB, with ECOG,.HTOO, and SWOG,
`gathered 180 pis (PS 0-2} havi~g. histologically documented TilT?
`adenocarcinomas without clinical evidence of progression through
`bowel waH or spread to lymph . node or distant site8 (ECOG/RTOG
`n'lgistered T3 as well), No tumor could be > 4crn rn di.ameter or
`el'compass> 40%. bowel wall clrct.Jrnferehce or be > tOcm from the
`dentate fine, Pts with tumor fixation, .anal cancer, otryer histologies. or
`prkJr theo1py were . inellgible. A ·tull'thick~ess tocal excision was
`attempted in 184/180 regist€miq pts: For thfs analysis, tlie 3 pts with T3
`lesions, were· not inCluded~ Forty eighfotner ptswere declared ineligH:ile
`liecause of; involvet!Jmargins, tumor> 4Cm; stage > T2, ana Stage< T1.
`'Of the remaining 113 eligible pts; the 60 T1 pis received no further
`treatmenta(ld.were observed for f~!Jrreh!ie anq surviVal on.~·spdei!ieq
`pt$ were treatE)(j \Nith ex.ternal beam ra?laiioil (')4do
`schedule: The 53
`. o begin ~ 6 week~ post focal exclsidna~
`'(:GY/30 fractions
`. . .
`~~F'li sopmgtm' IV bolus dl-3, 2.9'~F and th!:!n followed in a sltnlfar
`fashion. Surgical complications 'werrv:miniirial; .• wound (5%i, ~t·{4%),
`grade 3 +
`and GU (5%}: ChemoradlatJ~?n was
`(12~~); and
`toxicities ot.lymphocytopenla (2.5%);
`neutropenia {10%): After amediarr
`.· .......•... ··.·.
`..
`41113 pts
`have died of their malignant dtseas<t; Zl4 ha\lirigdistaht'J6CUrfE!nCe.?fliy.
`'(wo: pts have be<Jn succ~ssfully'treated for second c.Oforect<ll· rurrinr;>:
`· tmel,ices; .··both .haye
`Only 2/1.13 experienced
`undergone subSequent
`.·. . .• . ..... · . . ... . . . liVe: One pf wittY T2
`. .
`d\sease died .. · alter .43 ·mciijths ·rrom Utire!atedC?ttdiovasetila.r, aise£iSe.
`These d1;1ta indicate that sphincter p(~!3€i!Vation can be. ~f~le.vE;d wit~
`excellent cancer controf Wittioi.Jl saciifice 6! ana! fUnction ill selected pt$
`with superficial DRA.
`· ·
`
`D26
`
`*909
`to
`therapy: .appears superior
`Preoperative chemoractiation
`preoperative radiation alone .in the management .of clinical T3ff4
`recta! cancer.· N.R. Ahmad, P.R. Anno, O.A. Nagle, L.J. Rose, EP.
`Mitchell, .and R.D. Fry. Thomas Jefferson University, Philadelphia, PA
`Advantages of preoperative radiation therap-y (RT} in rectal cancer
`include increased resectabi!ity and sphincter-sparing surgery. This
`analysis assesses the influence of concurrent chemothero.py {CT} on
`the outcome. ot patients (pts) treated with preoperative RT for clinical
`stage T3/T4 (cT3!T4) rectal cancer. Two huhdred three pts with cT3fT4
`cancers received preoperative RT (median 55.8 Gy) followed by
`surgery. Forty-seven received concurrent GT (CRT group) and i 56 did
`not· (RT group}. CT consisted of protracted venous inf,usion 5-FU
`(300/mg/m''lday) in 32 pts, weekly bolus 5-FU (500/mg/m/week)
`leucovorin in 10 pts, and olher 5-FU-based. CT in 5 pis. Following
`surgery, 36 pts received adjuvant 5-FU CTfor3to 1S.months; 2B in the
`CRT groupand.10.in.the RT group. The median .follow,up times for the
`CRTcand RT groups were 36 and 49 months, respectively. Clinically
`fixed cancers constituted $7% (27/47) oUhe CRT group and 4B%
`(7511.56) of the RT group. Postoperative pathologic stage was T3iT4 in
`22/47 (47%) ofthe CRT group and 951156 (61%) ofth€;) BT group. Th!l
`5-year actuarial .local control (LC), distant metas!asls,free 'survival
`(DMFS) an.d overall survival (OS)ratesare.summarized.below;,
`
`LC%
`ilQ·
`96
`
`j)<
`ns
`
`DMFS% p <
`61
`q,02
`90
`
`RT
`C.RT
`
`*911)
`Multivariate analysis of mu;ue-uasecJ p:~~~~~~~c~;~::f~;~~e~,"'!l'"''·"·':v'
`IHU colprectal carcinoma,
`s'
`Shibata, G. Cangi, p,r. Lavin, A:Au4;;;;iiiri'6,
`Biostatistics, Inc., Framingham, MA and
`Center, Boston, MA
`Expression of molecules associated With the cell . cycl~ (p27Kip1, e<jc
`258), drug response {topoisomerase lio:}, d\fferentiatlon (sucrase(cid:173)
`isomaltase (S•!}}, ,or neoplastic transformation (DCC - deleted ih colon
`cancer) may define subsets ofpatientswhose outcome diffbi's from
`of !he stage-specific average. We tested this postulate iil 149
`with AJCC :stage. I! or m colorectal adenotarcili.oma resrec1:ea' tor
`without adjuvant. therapy at the De.acon&ss Hdspila! •
`1977. Median foltow-up is .115 mrm·ms :.w1m
`cancer: Tissue se~cuonsot p,ar<ifflil~e,nb,Ei.d<IM
`
`·
`
`Q~!§.£l9Jl1
`Abs.:ml
`Absent
`~bsept
`u
`
`· .. ~
`0:002
`().013
`0:053
`· .. 0.007
`. (t005
`0.153
`
`PRO(i}f$EDINGS\QIF:;t,\SCOVOLUMS 161997
`
`2.56a
`
`NEPTUNE GENERICS 1016- 00001
`APOTEX 1016-0001