D26
`
`*909
`Preoperative chemoractiation
`to
`therapy: .appears superior
`preoperative radiation alone Jn the management .of clinical T3ff4
`rectal cancer. N.R. Ahmad, P.R. Anne, D.A. Nagle, L.J. Rose. E.P.
`Mitchell, .and R.D. Fry. Thomas Jefferson University, Philadelphia, PA.
`Advantages of preoperative radiation theraf)'y (RT} in rectal cancer
`include increased resectabi!ity and sphincter-sparing surgery. This
`analysis .assesses the influence of concurrent chemotherH.py {CT} on
`the outcome- of patients (pts) treated with preoperative RT for clinical
`stage T3/T4 (cT3/T4) rectal cancer. Two hw1Clred three pts with cT3/T4
`cancers received preoperative RT (median 55.8 Gy} followed by
`surgery. Forty-seven received concurrent CT (CRT group) and 156 did
`not· (RT 1:1,roup}. CT consisted of protracted venous lnf,usion 5-FU
`(300/mg/m"lday) ln 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 cnor3to 18.months; 26 in the
`CRT group and .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 S7% (27/4TJ oUhe CRT group and 48%
`(75/1.56) of the RT group. Postoperative pathologic stage was T3/T4 in
`22/47 (47%) ofthe.CRT group and 951156 (61%) ofth€;) RT group. Th!l
`5-year actuarial .local control (LC), dlstant metastasls,free ·survival
`(DMFS) and over.all survival (OS) rates are .summarized. below;.
`0$%
`.. ··62
`$2
`
`LC%
`RT
`$()·
`96
`C.RT
`qrade 314 acute GUoxlcl.ty was signilicaotty greatei: int~~ CRT group
`(24%). vs. the. RT. group. (5%, p < 0:091" ;(). We cont;lude that in ,tbts.
`series, the DMF$ a[ld Og rates followip'g preoper9tfve CRT ap[:l!'iil'
`fiUperior h:i those obtained with preoperative RT a.l11rie ()( postoperat1ye
`CRT. The .incrt'lased acute toJ1icity of. CRT is acceptabre in· light of !he
`improved patient outl.'.Orne.
`
`DMFS% P<
`9,02
`61
`90
`
`j)<
`ns
`
`907
`Functional folate status as a prognostic indicator ot toxicity .in
`c!lnlcal trials of the multitargeted antifolate L Y23H314. Peter H..
`Robert H. Ailed', DonafdE. Thornton';· and Patricia A Thiem'.
`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 anti!umor 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 Giycinamide ribonucleotlde formyltrans!erase.
`folate status, based on serum concentrations of
`Functional
`homocysleine (HCYS), cystathione. (CYST AT); and meth}rtmalonic acid
`{MMA), was assessed in 116 patients participating in Phase 2 studies of
`l.:Y231514. This drug was administered as a iO-minute infusion once
`every 21 days. Samples were taken prior to initiation of· therapy and
`prior to .the start of each cycle. CTC toidcity scores (hematologic and
`non-hematologic} . .were assigned at !he end of uach cycfe. of therapy,
`Eight pts were found to be . fofate deficient (elevated HCYS. ahd
`CYSTAT and normal MMA}. Atlexperienced CTC grade.3 or4 toxicity
`whioh was primarily hematologic. From this .data, we would conclud\l'.
`that functional fotate staius appears to be.a.re!iable:prognostic inclicator
`of hematologtc ..toxicity that may be experienced from treatment . with
`LY2315-14. Fu~herinvestigation is warrant.ed to support this conclusion.
`
`GASTROINTESTtNAL CANCER
`. GaStttmintestinai Cai'l9er . . . ·.
`. .. · .
`Posterpiscussion Session, Sunday; May i 8, 1B97
`
`'
`
`*906
`· rect;tl aderio~arc:inoma: a
`Sphincter. sparing treatment for
`·Herndon', ANtf Burges.s', fl.
`phase U Intergroup .study. £ill.·
`Bled?y'; AH Russetf. ABBe.ns.o
`. . Mayer. 'Canqer
`..· ·
`... .
`..
`EJ.ildL~ukeit#a Group B (CALGB);zRadiation Therapy Oncology Group
`(RJ'OG);. }eastern •. Cooperative oncO!ogy Group JECQGJ; •southwest
`Oncology Group (SWOG).
`.
`.
`.
`.
`Uncontrolled series from single institutions have suggested. that the anal
`sphincter can be preserved in patients (pts) with.superficial.distal rectal
`adenocarcir:tomas .(ORA) but this concept has not been w~lldated in. a
`multlinstltutional setting. CALQB, with ECOG, HTOG, and SWOG,
`gatherecl t80 pis (PS 0·2} haviri°g histologically documented Tiff~
`.adenocarcinomas without clinical evidence of progression throug]')
`bowel wall or spread to lymph . node or distant sites (ECOG/RTOG
`registered TS as well). No turrior could be > 4C(l1 rn di.ameter or
`ef1Compass> 40% bowel \'\'all drcurnferehce or be >fO cm from the
`dentate fine; Pts with tumor fixation, .anal cancer, otryer histologies. or
`prr9r thecapy were. inellgible, A.'full· thickriess focal excision was
`attempted in 164/180 registered p!s: Fonhfs analysis, the 3 pts with JS
`lesions, were· no! included~ Forty eighfother ptswere decrared ineligible
`t)ecause of; involvedJmargins, tumor > 4cm; .stage> TZ, ahd Stage < T1.
`Oft!'ie remaining 113 eligible pts; the 60 T1 pts received no f.urther
`treatment a(ldwere observed.for re~j.lfrehce am:! surviv<ll on .a· specifioo
`schedule; The 53T2 pts were treateg V;rith ex.temal beam r:a~iafioil ()400
`i:;(SY/30 fraction~ 6days/week to begin re week~ posUocal ~xcisid':' ~t;id
`t?·F'l.J 50l)mg/rn' IV bolus dt-3, 2.9,:31.c and then followed m a s1m1far
`fashion. Surgica! complications ·w~reminirrial; .• wound (5%i, qt·{4%/,
`and GU. (5%}: Chemoradiati?n was· wen !Qlerawa with' grade 3 +
`tpxlcmes ot. lymphocytopenla (25%); d.iarrh13?J18%); skin \i?~~); and
`neutropenia (10%)~ After a median rollow~up of 24 rriontns,4/113 pts
`~ave (Red of their rrta!ignant dtseas<t;.Zl4 hallirigdislant•recum~nce.?nly.
`"f'..wo. pts have beem succ13ssfully' treated for second colorectaJ. tuniprs:
`Only 21113 experienced
`isolated local recurrences;.· both Mv:e
`undergone suooequent .re11ection .. ahd;'rerf)ain· alive:· Ohe•pf witfr ,T2·
`d\selise died after 43 months from urirelated c?rdiovascula.r)lisease.
`These d1;1ta indicate that sphincter' p(e)3€il'.Vation can .be .a.?~ieved with
`excellent cancer controf Witlioi.Jl sabiifice·olana! function in selected pt$
`with superficial DRA.
`·.
`·
`·
`·
`
`•910
`Multiv.arlate analysis of tissue.·based progno~ic rn~~kers .in
`IHI! colorectal carcinoma, .JM. J.~$..$..IJtJ,
`..•
`.·.
`l.C. Suinmerha.
`Shibata, (1 Cangi, P,T. Lavin, A.M. Mercurio;!=. Fogt, M. Loda, Boston;
`Biostatistics, Inc., Framingham, MA and Beth Israel Deaconess MediC.4l
`Center, Boston, MA.
`·
`Expression of molecules associated With the cell . cycle {p27Kip1, cqc
`258), drug response {topoisomerase Ila}, d\fferentiatlon (sucrase(cid:173)
`isomaltase (S•l})o, or rreoplastic transformation (DCC • deleted ih colon
`oancer) may define subsets of patients whose .outcome ·.differs from th?t
`of !he stage-specific average. We.tested this postulate in 149 patients
`with AJCC :stage .11 or m colorectal adenocarciri.oma resected• for nurl!f:
`withoutadjuvant therapy at the DeaconessHdspilal between 1965.ariit
`Hm .. Median fultow-up· is .. 1115 moriths•Wjth 511jf>. of patlentr,;.
`.
`cancer; Tissue sections of paraffin~t:JmbeJiaed tissues
`aritlf:.iodies and scored •tn a coded fashiorr as Absent
`tumor cEills;stainedX; Siandard clinleal\ Stage; am;J gra. e variable$
`i:issessed in Kapfan~Meier analyse$ (K'-M A}; Variables with a WIJ
`p value < 0.10 were the.n included in a Cox Prpportional)-lazards
`model:
`·
`· ·
`
`K:M,A
`pvalue
`.· ¥~!§.gQ.Q1
`.~
`G.066
`p<J7
`Absent
`0:002
`pee
`Absent
`(l.025
`Q.013
`0:053
`0.01.5
`A,bsept
`S'.I
`Stage
`0.007;
`.;0;()901
`H
`Gratje
`. (t005
`Not•Poor
`0:000·1
`···colon
`0.153
`Site
`0,057
`Age, ~ex, vasc1.ilar l~yw~ion; qd¢ 258; topbisom$rose 'i!Q:,'
`site ~\l<:!re qot signlficant ¢ovar1ati;>s. Expressloito
`·
`:~he '.risk of death from
`• · . .
`·
`riSk oJ cancer dqa:)h even
`.
`. .
`.
`strongly
`'in tne:C
`.
`. .... Jntra,umoral expres.sion ofp2
`:Strong prognostic factors and ()lay. identily:st?ge lb Ill 'tf
`patients withbeUi'Jr pro{}nosls,
`· · ·
`·
`·
`(SuppOrted by NCI Grant CA44704}
`
`PR061$EDINGS\Qlf:ASCOVOLUME 161997
`2.56a
`
`Wockhardt Exhibit 1016 - 1
`
`*909
`Preoperative chemoractiation
`to
`therapy: .appears superior
`preoperative radiation alone Jn the management .of clinical T3ff4
`rectal cancer. N.R. Ahmad, P.R. Anne, D.A. Nagle, L.J. Rose. E.P.
`Mitchell, .and R.D. Fry. Thomas Jefferson University, Philadelphia, PA.
`Advantages of preoperative radiation theraf)'y (RT} in rectal cancer
`include increased resectabi!ity and sphincter-sparing surgery. This
`analysis .assesses the influence of concurrent chemotherH.py {CT} on
`the outcome- of patients (pts) treated with preoperative RT for clinical
`stage T3/T4 (cT3/T4) rectal cancer. Two hw1Clred three pts with cT3/T4
`cancers received preoperative RT (median 55.8 Gy} followed by
`surgery. Forty-seven received concurrent CT (CRT group) and 156 did
`not· (RT 1:1,roup}. CT consisted of protracted venous lnf,usion 5-FU
`(300/mg/m"lday) ln 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 cnor3to 18.months; 26 in the
`CRT group and .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 S7% (27/4TJ oUhe CRT group and 48%
`(75/1.56) of the RT group. Postoperative pathologic stage was T3/T4 in
`22/47 (47%) ofthe.CRT group and 951156 (61%) ofth€;) RT group. Th!l
`5-year actuarial .local control (LC), dlstant metastasls,free ·survival
`(DMFS) and over.all survival (OS) rates are .summarized. below;.
`0$%
`.. ··62
`$2
`
`LC%
`RT
`$()·
`96
`C.RT
`qrade 314 acute GUoxlcl.ty was signilicaotty greatei: int~~ CRT group
`(24%). vs. the. RT. group. (5%, p < 0:091" ;(). We cont;lude that in ,tbts.
`series, the DMF$ a[ld Og rates followip'g preoper9tfve CRT ap[:l!'iil'
`fiUperior h:i those obtained with preoperative RT a.l11rie ()( postoperat1ye
`CRT. The .incrt'lased acute toJ1icity of. CRT is acceptabre in· light of !he
`improved patient outl.'.Orne.
`
`DMFS% P<
`9,02
`61
`90
`
`j)<
`ns
`
`907
`Functional folate status as a prognostic indicator ot toxicity .in
`c!lnlcal trials of the multitargeted antifolate L Y23H314. Peter H..
`Robert H. Ailed', DonafdE. Thornton';· and Patricia A Thiem'.
`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 anti!umor 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 Giycinamide ribonucleotlde formyltrans!erase.
`folate status, based on serum concentrations of
`Functional
`homocysleine (HCYS), cystathione. (CYST AT); and meth}rtmalonic acid
`{MMA), was assessed in 116 patients participating in Phase 2 studies of
`l.:Y231514. This drug was administered as a iO-minute infusion once
`every 21 days. Samples were taken prior to initiation of· therapy and
`prior to .the start of each cycle. CTC toidcity scores (hematologic and
`non-hematologic} . .were assigned at !he end of uach cycfe. of therapy,
`Eight pts were found to be . fofate deficient (elevated HCYS. ahd
`CYSTAT and normal MMA}. Atlexperienced CTC grade.3 or4 toxicity
`whioh was primarily hematologic. From this .data, we would conclud\l'.
`that functional fotate staius appears to be.a.re!iable:prognostic inclicator
`of hematologtc ..toxicity that may be experienced from treatment . with
`LY2315-14. Fu~herinvestigation is warrant.ed to support this conclusion.
`
`GASTROINTESTtNAL CANCER
`. GaStttmintestinai Cai'l9er . . . ·.
`. .. · .
`Posterpiscussion Session, Sunday; May i 8, 1B97
`
`'
`
`*906
`· rect;tl aderio~arc:inoma: a
`Sphincter. sparing treatment for
`·Herndon', ANtf Burges.s', fl.
`phase U Intergroup .study. £ill.·
`Bled?y'; AH Russetf. ABBe.ns.o
`. . Mayer. 'Canqer
`..· ·
`... .
`..
`EJ.ildL~ukeit#a Group B (CALGB);zRadiation Therapy Oncology Group
`(RJ'OG);. }eastern •. Cooperative oncO!ogy Group JECQGJ; •southwest
`Oncology Group (SWOG).
`.
`.
`.
`.
`Uncontrolled series from single institutions have suggested. that the anal
`sphincter can be preserved in patients (pts) with.superficial.distal rectal
`adenocarcir:tomas .(ORA) but this concept has not been w~lldated in. a
`multlinstltutional setting. CALQB, with ECOG, HTOG, and SWOG,
`gatherecl t80 pis (PS 0·2} haviri°g histologically documented Tiff~
`.adenocarcinomas without clinical evidence of progression throug]')
`bowel wall or spread to lymph . node or distant sites (ECOG/RTOG
`registered TS as well). No turrior could be > 4C(l1 rn di.ameter or
`ef1Compass> 40% bowel \'\'all drcurnferehce or be >fO cm from the
`dentate fine; Pts with tumor fixation, .anal cancer, otryer histologies. or
`prr9r thecapy were. inellgible, A.'full· thickriess focal excision was
`attempted in 164/180 registered p!s: Fonhfs analysis, the 3 pts with JS
`lesions, were· no! included~ Forty eighfother ptswere decrared ineligible
`t)ecause of; involvedJmargins, tumor > 4cm; .stage> TZ, ahd Stage < T1.
`Oft!'ie remaining 113 eligible pts; the 60 T1 pts received no f.urther
`treatment a(ldwere observed.for re~j.lfrehce am:! surviv<ll on .a· specifioo
`schedule; The 53T2 pts were treateg V;rith ex.temal beam r:a~iafioil ()400
`i:;(SY/30 fraction~ 6days/week to begin re week~ posUocal ~xcisid':' ~t;id
`t?·F'l.J 50l)mg/rn' IV bolus dt-3, 2.9,:31.c and then followed m a s1m1far
`fashion. Surgica! complications ·w~reminirrial; .• wound (5%i, qt·{4%/,
`and GU. (5%}: Chemoradiati?n was· wen !Qlerawa with' grade 3 +
`tpxlcmes ot. lymphocytopenla (25%); d.iarrh13?J18%); skin \i?~~); and
`neutropenia (10%)~ After a median rollow~up of 24 rriontns,4/113 pts
`~ave (Red of their rrta!ignant dtseas<t;.Zl4 hallirigdislant•recum~nce.?nly.
`"f'..wo. pts have beem succ13ssfully' treated for second colorectaJ. tuniprs:
`Only 21113 experienced
`isolated local recurrences;.· both Mv:e
`undergone suooequent .re11ection .. ahd;'rerf)ain· alive:· Ohe•pf witfr ,T2·
`d\selise died after 43 months from urirelated c?rdiovascula.r)lisease.
`These d1;1ta indicate that sphincter' p(e)3€il'.Vation can .be .a.?~ieved with
`excellent cancer controf Witlioi.Jl sabiifice·olana! function in selected pt$
`with superficial DRA.
`·.
`·
`·
`·
`
`•910
`Multiv.arlate analysis of tissue.·based progno~ic rn~~kers .in
`IHI! colorectal carcinoma, .JM. J.~$..$..IJtJ,
`..•
`.·.
`l.C. Suinmerha.
`Shibata, (1 Cangi, P,T. Lavin, A.M. Mercurio;!=. Fogt, M. Loda, Boston;
`Biostatistics, Inc., Framingham, MA and Beth Israel Deaconess MediC.4l
`Center, Boston, MA.
`·
`Expression of molecules associated With the cell . cycle {p27Kip1, cqc
`258), drug response {topoisomerase Ila}, d\fferentiatlon (sucrase(cid:173)
`isomaltase (S•l})o, or rreoplastic transformation (DCC • deleted ih colon
`oancer) may define subsets of patients whose .outcome ·.differs from th?t
`of !he stage-specific average. We.tested this postulate in 149 patients
`with AJCC :stage .11 or m colorectal adenocarciri.oma resected• for nurl!f:
`withoutadjuvant therapy at the DeaconessHdspilal between 1965.ariit
`Hm .. Median fultow-up· is .. 1115 moriths•Wjth 511jf>. of patlentr,;.
`.
`cancer; Tissue sections of paraffin~t:JmbeJiaed tissues
`aritlf:.iodies and scored •tn a coded fashiorr as Absent
`tumor cEills;stainedX; Siandard clinleal\ Stage; am;J gra. e variable$
`i:issessed in Kapfan~Meier analyse$ (K'-M A}; Variables with a WIJ
`p value < 0.10 were the.n included in a Cox Prpportional)-lazards
`model:
`·
`· ·
`
`K:M,A
`pvalue
`.· ¥~!§.gQ.Q1
`.~
`G.066
`p<J7
`Absent
`0:002
`pee
`Absent
`(l.025
`Q.013
`0:053
`0.01.5
`A,bsept
`S'.I
`Stage
`0.007;
`.;0;()901
`H
`Gratje
`. (t005
`Not•Poor
`0:000·1
`···colon
`0.153
`Site
`0,057
`Age, ~ex, vasc1.ilar l~yw~ion; qd¢ 258; topbisom$rose 'i!Q:,'
`site ~\l<:!re qot signlficant ¢ovar1ati;>s. Expressloito
`·
`:~he '.risk of death from
`• · . .
`·
`riSk oJ cancer dqa:)h even
`.
`. .
`.
`strongly
`'in tne:C
`.
`. .... Jntra,umoral expres.sion ofp2
`:Strong prognostic factors and ()lay. identily:st?ge lb Ill 'tf
`patients withbeUi'Jr pro{}nosls,
`· · ·
`·
`·
`(SuppOrted by NCI Grant CA44704}
`
`PR061$EDINGS\Qlf:ASCOVOLUME 161997
`2.56a
`
`Wockhardt Exhibit 1016 - 1
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