`
`0
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`- ~
`
`August 1, 1994
`Volume 74
`Number3
`ISSN 0008-543X CANCAR
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`1 of 18
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`Celltrion, Inc., Exhibit 1007
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`
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`-
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`991
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`994
`
`995
`
`1000
`
`1 006
`
`1013
`
`SA
`
`cer
`
`S u p pleme nt to
`August 1 , 1 9 9 4
`Volume 74
`Numbe r 3
`
`An l nterdisciplina
`~n:,le;~ational ]our'Zz1 of the
`rzcan Cancer Society
`
`Contents
`
`•
`. 1
`d
`ren s . nc1dence, Mortality, and Survival
`Breas t Cancer T
`.
`ward f. So11d1k
`Ed
`
`.
`h
`a •on ec mques for the Characterization of Breast
`Fine Needle Aspir t • T
`C<lncers
`f'.·::: ·M~ri~ Ljung, Kare11 Chew, Guoren Deng, Kouji Matsumura Fred Waldman and
`'
`'
`• . . ,.,, •· ~·1111th
`
`'Y~• get~J T oxin s as Antica nce r Agents
`C!ay B. Siesall
`Familia l Breast Cancer: Approaching the Isolation of a Susceptibility
`Gene
`Barbara L. Weber, Kenneth/. Abel, Larry C. Brody, Wendy L. Flejter, Settara c.
`Chandrasekharappa, Fergus/. Couch, Sofia D. Merajver, and Francis S. Collins
`
`CANCER (ISSN 0008 -543X) is published twice a month for the ~erican Cancer Society, ~y ). B. Lippincott Co~pany, at 12107 Insurance Way, Suite 114, Hagers(cid:173)
`~own, MD 21740. Business offices are located at 227 East Washington Squar:e: Ph1lad~lph1a, PA 19106. ©. C~pynght 199~ by the American Cancer Society. Printed
`m the USA. Serund class postage paid at Hagerstown, Maryland, and at add1uonal mailing o~ces. Subscn phon information, o rders, or changes of address (except
`Japan) 12 107 Insurance Way, Sui te 114, Hagerstown, MD 21740, or call l-800-638 -3030; in Maryland, call collect 301-714-2300. In Japan, contact lgaku-Shoin,
`Ltd.,S-24-3 Hongo, Bunkyo ku, Tokyo. l 13-91 Japan. Annual subscription r.ttes: U.S. $125.00 indi~idual, $205.00 institution, $83.75 resident/student (U.S. only);
`Ca~ada and Mexico $205.00 individual, $320.00 institution; all other coun.triesexcept !d~an $261.00 mdivid.ual, ~376.00 i.nstitulion (pri~es include 556.00 air freight
`delivery; air freight delivery occurs within 7-21 days worldwide). lntemahonal subscr1p~ons.must be prepaid: Single cop1~ $13.00. (~ates are subject to change.) In
`Japan, contact Jgaku·Shoin, Ltd., 5-24·3 Hongo, Bunkyo·ku, Tokyo, 113· 91 J~pan. c.0~1es w1ll be replaced wtthout charge 1hhe publisher receives a.request ,,,;thin
`60 days of the mailing date in the U.S. or within 5 month~ in ~II other countnes. Op1111ons expressed by the authors are th~1r own and not necessanly those of the
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`POSTMASTER; Send address changes to CANCER, P.O. Box 1550, Hagerstown, MD 21740.
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`€J T~t printed on add·free paper.
`
`2 of 18
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`Celltrion, Inc., Exhibit 1007
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`
`
`Cancer Supplement to
`
`August 1 • 1994
`Volume74
`Number3
`
`Contents conlinutd
`
`I
`
`l
`
`1021
`
`1026
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`1030
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`1045
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`1050
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`1055
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`1063
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`1070
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`1078
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`1085
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`duction Pathways and Angiogenic
`.
`Gene Therapy through S1gnatl _Tr~::gets in Breast Cancer
`Growth Factors as Therapeu ic
`L J
`e and
`Adrian L. Harris, Steve Fox, Roy Bicknell, Russell Leek, Michele Relf, Sue e eun '
`Louikas Kaklamanis
`
`d Hormone Resistance
`·
`Estrogen Receptor Mutagenes1s an
`Suzanne A. W. Fuqua
`
`Role of Mesenchymal-Epithelial Interactions in Normal and Abnormal
`Development of the Mammary Gland and Prostate
`Gerald R. Cunha
`
`Stromelysin-3 in Stromal Tissue as a Control Factor in Breast Cancer
`Behavior
`Paul Basset, Catherine Wolf, Nicolas Rouyer, Jean-Pierre Bellocq, Marie-Christine Rio, and
`Pierre Chambon
`
`Conjugated Linoleic Acid: A Powerful Anticarcin~'~o:;:,-, fro m Animal Fat
`Sources
`Clement Ip, fosei;r: A Scimeca, and Henry J. Thompson
`
`lnterrelaticil.fiMp Between Dietal'y Lipids and Calories and Experimental
`Mammary Gfar.d Tumorige nes is
`Clifford W. Welsch
`
`Dietary Carcinogens and Mammary Carcinogenesis: ind'f.;i;·~icn of Rat
`Mammary Carcinomas by Administration of Heterocvc lic Amines in
`Cooked Foods
`Minako Nagao, Toshikazu Ushijima, Keiji Wakabayashi, Masako Och iai, !iiromi Kushida,
`Takashi Sugimura, Ryohei Hasegawa, Tomoyuki Shirai, and Nobuyuki I to
`
`Some Perspectives on the Nutritional Aspects of Breast Cancer
`Research: Food-derived Heterocyclic Amines as Etiologic Agents in
`Human Mammary Cancer
`Elizabeth G. Snyderwine
`
`Dietary Fat and Breast Cancer Risks: An Epidemiologic Perspective
`Geoffrey R. Howe
`
`Prospective Studies of Diet and Breast Cancer
`Walter C. Willett and David/. Hunter
`
`3 of 18
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`Celltrion, Inc., Exhibit 1007
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`
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`Cancer
`
`S upplement to
`A ugust 1 , 1 994
`Volume74
`N umber 3
`
`7A
`
`.
`t C
`Alcohol and Bre
`from Here?
`as ancer: Where Are We Now and Where Do We Go
`
`Arthur Schatzkin and Matthew P. Longnecker
`
`Steroid Hormones and Risk of Brea st Cancer
`.
`Barbara S Hulka Ed'
`·
`,
`zson T. Liu, and Ruth A. Lininger
`~he Effect of Dietary Fat and Fiber on Serum Estrogen Concentrations in
`remenopausal Women under Controlled Dietary Conditions
`Barry. R. Goldin, Margo N. Woods, Donna L. Spiegelman, Christopher Longcope, Ann
`MG orbnll-LaBrode, Johanna T. Dwyer, Lisa J. Gualtieri, Ellen Hertzmark, and Sherwood L.
`or ach
`
`Current Trials and Future Directions of the Eastern Coope rative Oncology
`Group Breast Cancer Committee
`William C. Wood
`
`Cu~f"ent Trials a nd Future Directions of the Southwest Oncology Group
`Br-:;,~,,.~ Ct:mcer Committee
`C. i.». '·' Or.home
`
`fiw :; .~.:fft <m d Future Projects of the International Breast Cancer Study
`Gm..tp
`Anm Guldfi irsch, Richard D. Gelber, Monica Castiglione, Karen N. Price, Carl-Magnus
`Rudenstam, furij Lindtner, John Collins, Hans-/iirg Senn, Kurt W. Brunner, Enzo Galligioni,
`Franco Cavalli, Anne Gudgeon, Hernan Cortes-Funes, Martin Tattersall, Giovanni Marini,
`Michael Byrne, Ray Snyder, John F. Forbes, Christoph Hiirny, and Alan Coates for the
`Jntemational Breast Cancer Study Group
`
`Clinical Cooperative Trials of the National Cancer Institute of Canada
`Clinical Trials Group Breast Cancer Site Group
`Kathleen I. Pritchard
`
`Randomized Adjuvant Breast Cancer Trials in Sweden
`Lars E. Rutqvist
`
`Cooperative Breast Cancer Trials Organized by the Unit ed Kingdom
`Coordinating Committee on Cancer Research
`Jack Cuzick, Jean Mossman, and Helen Stewart
`
`Contents continued
`----------:-1~0:9~0~~-===~--------------~~--~~~~--------~~~
`Anthropomet
`Rachel Ball d Bry and Breast Cancer: Body Size- A Moving Target
`ar - arbaslt
`
`1101
`
`1111
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`1125
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`1132
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`1135
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`1139
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`1150
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`1156
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`1160
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`4 of 18
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`Celltrion, Inc., Exhibit 1007
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`Cancer
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`Sup plement t o
`August 1 • 1994
`Volume74
`Number3
`
`Contents continued
`
`Chemotherapeutic Agents for Breast Cancer
`N
`" d
`ew
`Jeffrey S. Abrams, Timothy D. Moore, and Michael Frie man
`
`Dose Intensity and High Dose Therapy: Two Different Concepts
`Robert B. Livingston
`
`. H ' h R' k Women for Breast
`•
`is
`Psychol ogical A spects of Momtormg 19
`.
`Cancer
`Henry T. Lynch, Jane Lynch, Tlieresa Conway, and Mattlzew Severm
`
`Instructions for Authors
`
`The Instructions for Authors section is in the July 1, 1994, issue. Please refer to the
`Instructions for Authors for preparation of manuscripts to submit to Cancer.
`
`5 of 18
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`Celltrion, Inc., Exhibit 1007
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`
`
`1104
`
`Nevv Chemotherapeutic Agents
`for Breast Cancer
`Jeffrey 5. Abrams, M.D., • Timotlry D. Moore, M.D.,t a11d Micl1nel Fried111n11, M.D.t
`
`r:;:he drug discovery proi;rnms of the Nalional Cancer In·
`slllute and the pharmnccullcal industry rnccnlly hove
`provided oncologists with 11 wide arrny of new chemo·
`thera peu tic ai;enls that have considerable poten tial for
`breast cancer treatment. t•oremost among these new
`agents arc the taxancs, of which paclitaxcl and docetaxcl ,
`the only members of this class currently in clinica l use,
`have been nssocinted with Impressive res11onse rates In
`patients with metastatic disease. Importantly, they dis·
`play some evidence clini cally of not being cross-resistant
`with the anthracycli nes. Efforts now are being directed
`toward optimizing dose and schedu le in the metastatic
`setting while integrating these agents into s tandard odju(cid:173)
`vant regimens.
`Other agents that have undergone Phase II testing in
`breast cancer include vlnorclbinc, cdatrexate, and losox(cid:173)
`nntronc. It remains to be determined, however, whether
`these drugs possess substantial advantages over other
`members of their class. Newer compounds, s uch os pyra(cid:173)
`zoloacridinc, ICI 01G!J4, topoisomerasc-J inhibilors, tem·
`ozolomide, pcnclomidine, fumni;illin (TNP-470), and
`differentiators like the rctinoids, hold substantial prom(cid:173)
`ise because of thei r unique mechanisms of action; how(cid:173)
`ever, Phase II tcslins of th ese agents is just beginning. Al·
`though alternative approaches lo treatment , such ns gene
`therapies, monoclonal antibodies. and growth factor in·
`hibitors, arc likely to have u positive impact, ii is proba(cid:173)
`ble that progress will best be made by combining these
`s trategics with chcmotherupy. Therefore, oonlinuntion of
`t he search for more clfoctlve chemotherapeutic agents
`should remain a high prior~ Cancer 1994; 74:1164-76.
`
`A review of the recently updated international meta·
`analysis' of adjuvant therapy for breast cancer indicates
`that chemotherapy has the potential to save more lives
`from this disease than from any other malignancy.
`These pooled results, along with similar findings from
`National Cancer Institu te (NCl)-sponsored cooperative
`group trials, verify that cytotoxic therapy developed
`first in th e metastatic setting provides a significa nt sur·
`viva! advantage when applied to earlier stages of dis·
`case. Nonetheless, systemic treatment of breast cancer
`is far from optimal. Cytotoxic or hormonal therapy for
`metastatic disease is rarely curative, whereas a substan(cid:173)
`tial number of women continue to suffer recurrences
`and die, despite receiving adjuvant therapy. Clearly,
`there remains a pressing need to identify active new
`compounds to supplement those currently in use.
`Jn response to this need, the Division of Cancer
`Treatment of the NCI and the pharmaceutical industry
`arc presenting oncologists with a plethora of new che·
`motherapcutic agents/ many of which possess unique
`mechanisms of action. Several of these drugs already
`have demonstriltcd significant breast cancer activity,
`while others show potential in laboratory models. This
`summary reviews some of the promising new agents for
`breast cancer patients, including discussions of their
`mechanisms of action and pharmacokinetics, as well as
`the initial results of clinical trials of these agen ts. It con(cid:173)
`cludes with a discussion of strategics that have been
`adopted to expedite their clinical development.
`
`Key words: chemotherapy, taxol, laxotcrc, vinorelbine,
`cdat rcxate.
`
`Paclitaxel
`
`Presented at the Conference on BreJst Cancer RC'seMch: Current
`fssucs-Fulurc Directions. All•nl•. Georgia, April 25-28, 1993.
`From the @inical lnvcs11i;alions Bra~and the flnvcsllga(cid:173)
`tional Drug Branch~ the ic..nccr Therapy Evaluation Prosram, Oivi·
`sion or C..ncerTrea1men1/N•t1onal Cancer lnsti1u1e, Dethcsc:la, Mary·
`-
`••nP ·-
`Address for roprin1s: Jcllrey S. Abrams, M.D. C.nctr Th•r.py
`Ev.iluJtion Prognm. o;vision of C.incerTreatmt'nt. N.ition.:?,I C.incer
`lnslllutc, Room 74 t, llxecu1ivc l'I••• North, llelhe&la, M~892,;'
`~
`R•ceived March 10, 1994; acccplcd March 16, 1994.
`
`The taxanes nrc one of the most exciting new classes of
`chemotherapeutic agents to be developed. The proto·
`type of this novel class, paclitaxel (Taxol, Bristol-Myers
`Squibb, Princeton, NJ), was approved by the Food a.nd
`Drug Administration for treatment of refractory ovarian
`cancer patients in December 1992, but its potential in;
`dications are expanding rapidly. Previous reviews>.
`documented the difficult formulation of paclitaxel and
`discuss the problems that complicated its 30-yea.r de(cid:173)
`velopment.$ Fortunately, a collaborative effort on the
`
`-
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`6 of 18
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`Celltrion, Inc., Exhibit 1007
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`
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`New Chemotherapeutic /\gents for Breast Cancer/ l\lmims ct al.
`
`1165
`
`Table l. l ncidencc of Paclilaxel Toxicity
`in Single-Agent Studies"
`
`Study
`
`Incidence(%)
`
`part of the NCI and the Bristol-Myers Squibb Company
`has ma naged to overcome most problems.
`Paclitaxel exhibits broad but modest activity in mu·
`rine and human tumor xenograft models (National
`Cancer Institute, clinical brochure on Taxol (IND22856,
`NSC125973], 1990). Interest in this compound was
`heightened when its unique mechanism of action was
`discovered by Horwitz and colleagues.• These investi·
`gators noted that. paclitaxel stabilized the microtubulcs
`and enhanced their assembly, in contrast to the pre(cid:173)
`viously available spindle poisons (colchicine and vinca
`alkaloids}, which disrupt such assembly. Microtubules
`are active in cellular motility and division, intracellular
`transport, and secretion of protein products. In addi(cid:173)
`tion, their stabilization impairs the essential equilibrium
`between assembly and disassembly required for many
`dynamic cellular processes. In tumor cells, the histologic
`correlate of taxane cytotoxicity is represented by the ap·
`pearance of abnormal microtubulc bundles, which ac·
`cumulate during both interphase and mitosis.'
`Phase I trials with paclitaxel began in 1984, and nu(cid:173)
`11 The develop·
`merous studies have been published.8
`"
`ment of paclitaxel initially was hindered by the occur(cid:173)
`rence of hypersensitivity reactions (HSRs}. 12 A prolon(cid:173)
`gation of the duration of administration to 24 hours
`combined with the instituti_on of a premedication regi(cid:173)
`men consisting of hydrocortisone, antihistamines, and
`H, blockers greatly reduced the incidence of HSRs to
`approximately 2% (Bristol-Myers Squibb Co., unpub·
`lished data, 1992). It remains unclear whether the phe(cid:173)
`nomenon is mediated primarily by paclitaxel itself or
`the cremophor vehicle (polyoxyethylated castor oil).
`With effective prophylaxis of the HSRs, neutro(cid:173)
`penia became the dose-limiting toxicity (DLT). Fortu(cid:173)
`nately, paclitaxel is relatively platelet sparing. Attempts
`to overcome neutropenia have led to the use of human
`granulocyte colony stimulating factor (G·CSF). Inclu(cid:173)
`sion of G-CSF has permitted paclitaxcl dose escalations
`up to 250 mg/m2
`." Above this level, a dose-limiting
`peripheral neuropathy supervenes.
`Acute toxicities associated with paclitaxel and their
`relative frequencies are shown in Table 1 (Bristol-Myers
`Squibb Co., unpublished data, 1992). Because of the
`HSRs, cardiac monitoring was mandatory in the early
`trials with this drug. Asymptomatic bradycardia was
`the most frequent finding, but symptomatic supraven(cid:173)
`tricular and ventricular tachycardias were seen occa·
`sionally. Analysis of this data suggest that cardiac mon(cid:173)
`itoring is unnecessary in people without a history of
`cardiac isclwmia. is However, NCI-sponsored trials
`have excluded patients with a history of ischemia or
`conduction disturbance, so treatment recommendations
`for this cohort remain uncertain. The Eastern Coopera·
`tive Oncology Group currently is conducting a trial spe·
`
`92
`67
`
`93
`26
`
`27
`10
`
`90
`24
`35
`19
`34
`3
`
`41
`2
`
`JO
`23
`
`Oonemarrow
`NeutropeniJ
`<2,000/mm'
`<500/mm'
`Lcukopcni.i
`<4,000/mm'
`< 1,000/mm'
`111rornbocy1openio
`<100,000/mm'
`< 50,000/mm'
`Ancmi.1
`< 11 g/dl
`< 8 g/dl
`Infections
`Ulccding
`Pocked cell tr.insfusions
`Platelet transfusions
`Hypersensitivity fCJctions•
`/lny
`Severe
`Cardiov.>SCUldr
`Or~dyc.lrdi1.1 during infusion
`Hypotension during infusion
`Severe cardiov.tscul3r events
`/lbnorm•I EKG
`All p.11icnts (n ~ 402)
`Patients with normal baseline (n u 236)
`Perlphcr•I neur<>p•lhy
`Any symptoms
`Severe symptoms
`Myalgia/arthrol&i•
`Any syrnp1oms
`Severe symptoms
`Gastrointestinal
`N.-iuseot and vomiting
`Diarrhea
`Mucositis
`A loped•
`Hcpatic (p..:itients with normotl b.lseline Jnd
`onSludy dota
`Bilirubin clcv.iions (n = 370)
`Alkaline phosphalasc clcvotions (n b 293)
`23
`AST (SCOT) elevations (n • 287)
`16
`EKG; dcctroc.udiogr.>m; AST: a~p3t1.lt<! lr.lns..1min.ise; SCOT: K'rum gJul.\ll'llnc
`ox111o.'lcetic 1r:.nsJmin.i.s~.
`•All fh\tients r«el"cd pr~m~k<llion ttgimcn.
`
`30
`19
`
`62
`
`55
`
`59
`n
`39
`82
`
`cifically designed to test paclitaxel in such patients that
`should provide treatment guidelines in the future.
`Currently, the optimal duration of taxol administra·
`16
`tion is being investigated (Table 2). 11
`· 11 To adminis·
`·"·
`ter paclitaxel in an outpatient setting, a 3-hour infusion
`is used. Conversely, other investigators now are pro(cid:173)
`longing the infusion schedule to 72 hours, 18 96 hours, 17
`
`7 of 18
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`Celltrion, Inc., Exhibit 1007
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`11GG
`
`CANCER Supplement A11g11st t, 1994, Volume 74, No. 3
`
`Table z. Suggested Single-Agent Taxol Dose (mg/m'}
`According to Schedule and G·CSF Usage
`
`G-CSF
`
`3 hr
`
`24 hr
`
`96hr
`
`l4d>y
`
`Undenvar
`140 (17)
`175 (14)
`175 (lo)
`No
`Unde-rway•
`NA
`250 (11)
`NA
`Yes
`G~CSJ:: g.r.lnulocyl~ coluny·$1imul.:iting foctur; NA: not .lpptk~blc.
`· Ph.:isc fl )tudy und~rw.ly.
`
`and, most recently, 14 days U O'Shaughnessey, M.D.,
`personal communication, August l 993).20 This latter
`approach may allow paclitaxel to effect more of the
`slowly cycling cells commonly found in solid tumors.
`Furthermore, prolonged drug exposure has been shown
`in vitro to be capable of overcoming I' glycoprotein-me(cid:173)
`diated paclitaxel resistance. 19
`Incomplete information is available on mechanisms
`of paclitaxcl clearance from the body. It is known that
`greater than 95% of the circulating drug is extensively
`protein bound. Hepatic and biliary clearance appear to
`be the predominant mechanisms of drug clearance.'·22
`In fact, Wilson et al. 17 have shown that patients with
`coexisting liver dysfunction have a significantly re(cid:173)
`duced total body clearance of paditaxel and suffer se(cid:173)
`vere toxicity requiring dose reduction.
`Recent pharmacokinetic studies of paclitaxel dem(cid:173)
`onstrated that drug clearance decreases with increasing
`doses (from 135 mg/m2 to 300 mg/m2).n22 This sug(cid:173)
`gests a saturable elimination process, which implies that
`paclitaxel's pharmacokinetics are nonlinear. If this is the
`case, a substantial amount of variation in drug exposure
`(i.e., area under the curve) might exist for different
`doses or infusion schedules.
`Single-agent Phase Ir trials of paclitaxel in breast
`cancer patients (Table 3)' 6•17•1,_,6 have indicated sub(cid:173)
`stantial activity in patients with breast cancer. Gener(cid:173)
`ally, the response rates a.re lower in those who have re-
`
`ceived extensive prior treatment. These responses have
`been reasonably durable, even though few have been
`complete. Most importantly, patients dearly have re(cid:173)
`sponded to paclitaxel after progression on doxorubicin.
`This lack of clinical cross-resistance should be exploit(cid:173)
`able in designing regimens that combine both of these
`active agents.
`Investigators at the NCl18 found that a 60-mg/m1
`dose of doxorubicin and a 180-mg/m2 dose of paclitaxel
`given concurrently over 72 hours in combination with
`G-CSF every 3 weeks resulted in unusual toxicity.
`Grade 3-4 diarrhea and abdominal pain, thought to be
`secondary to typhlitis (thickening of the cecum on com(cid:173)
`puted tomography), occurred much below the single(cid:173)
`agent maximum tolerable dose for paclitaxel in this trial.
`The overall response rate was 72% (28 of 39 patients) in
`these doxorubicin-naive patients, but only 10% (4 of 39
`patients) had complete responses. Pharmacokinetic
`studies indicated that altered drug clearance does not
`explain the enhanced toxicity observed with this com(cid:173)
`bination.
`Investigators at the University of Texas M. D. An(cid:173)
`derson Cancer Center" encountered severe stomatilis
`when the administration of paclitaxel (125 mg/ml over
`24 hours of continuous infusion on day 1) preceded that
`of doxorubicin (48 mg/m' over 48 hours of continuous
`infusion on days 2-3) with C-CSF (S µg/kg/day 011
`days 5-19). The opposite sequence currently is being
`studied and has allowed the escalation of the doxorubi·
`cin dose (60 mg/m2
`} as well as the paclitaxel dose (180
`mg/m2
`).
`A Phase Ill test of this combination recently has
`been started by the Eastern Cooperative Oncology
`Group. This study, in women with untreated metastatic
`breast cancer, is comparing single-agent doxorubicin
`therapy (60 mg/m2 every 3 weeks for 8 cycles) versus
`treatment with paclitaxel (175 mg/m1 every 3 weeks for
`
`Tobie 3. Phase II Trials ofTaxol ± G-CSF in Advanced Dreast Cancer
`Group
`(.rd ere nee
`No.)
`
`No.of
`evaluable
`pa lien ts
`
`Prior <hcmother.py
`
`Dose and schedule
`
`Adj- 14
`Mets-II
`250 mg/m' + G·CSF
`Adj-16
`140mg/m'ovcr96 hr infusion
`Mcts-22
`136 mg/m' over3 hr vs. 175 mg/m'
`Adj- 38
`ovcr3 hr
`Mets-41
`150mg/m1
`Mets-12 (:. 3 prior regimens)
`Mets- 72 (median: 2 prior
`250 mg/m' + G·CSF (200 mg/m' if
`> 1 prior chemotherapy)
`regimens)
`C-CSr:: gr.:inulocyle rolony·stimufoting foe.tor; CR: compltle response; PR: p.>rH.:il response; NA: not av.iilabll?; Adj: :idjuv.:inl; Mets: metJst~ttc:": MOA: M. O. And<'f(cid:173)
`son; MSKCC: Memorial Slo.bn·Kcttering C~mcer Cc-nt('t; NCI. Nation.ti Cancer ln,ti1u1c; OMS: Oristol·Myers Squibb.
`• R.:prcsenls ov~r.:ill te5ponse r.t1c on both 11rms.
`
`MOAn
`
`250mg/m2
`
`MSKCC"
`NCI"
`BMS"
`
`MOA"
`MSKCC"
`
`25
`
`26
`22
`111
`
`12
`72
`
`No. of responses
`
`CR('t.)
`
`l'R('fo)
`
`Duration of
`rtsponse
`(range) (mo)
`
`3 (12)
`
`II (44)
`
`8(3-19)
`
`3 (12)
`I (5)
`3•(3)
`
`0
`2 (3)
`
`13 (50)
`11 (50)
`27• (24)
`
`4+(1-8+)
`NA
`NA
`
`3 (25)
`18 (25)
`
`NA
`4.5+ (1 - 7+)
`
`8 of 18
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`New Chemolhcrapeutic Agents for Breast Cancer/ llbrams et al.
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`1167
`
`8 cycles) versus the combination of doxorubicin (SO
`mg/m2 intravenous [IV) bolus) followed by paclitaxel
`(150 mg/m2 over 24 hours) plus G-CSF for 8 weeks.
`Patients in the single-agent arms can be crossed-over to
`the alternate arm at progression of their disease.
`
`Docetaxel
`
`The effectiveness of paclitaxel has stimulated the search
`for other taxanes that might be easier to produce, less
`toxic, or more effective. Docetaxel (Taxotere, Rhone(cid:173)
`Poulcnc Rorer Pharmaceuticals, Inc., Collegeville, PA)
`is the first such congener to be tested in clinical trials. It
`is a sernisynthetic molecule made in part from the nee·
`dles of the European yew tree and then modified chem·
`ically with a synthetic side chain.28 Docetaxel promotes
`microtubule assembly in a fashion similar to that of
`paclitaxel, but in contrast to paclitaxel, it is more po(cid:173)
`tcnt, 2'' resulting in lower maximum tolerable doses in
`Phase l trials.30· 3' Phannilcologically, docetaxel is
`cleared from the body primarily via the biliary route,
`mirroring the clearance of paclitaxel.3
`' It is more water
`soluble than paclitaxel, however, permitting its formu·
`lation in polysorbate-80 rather than crcmophor. None·
`theless, HSRs have been noted. Although these are usu·
`ally milder than the reactions seen with paclitaxel, pre·
`medication is recommended.3s
`Docetaxel's toxicity profile is similar to that of
`paclitaxel, yet there appear to be some important differ·
`ences. Neutropenia is once again the dose-limiting toxi·
`city.36
`0 Peripheral neuropathy, mucositis, alopecia,
`·•
`and mild nausea and vomiting likewise have been
`noted. Skin toxicity, however, characterized by local·
`ized or diffuse erythema with skin thickening and occa·
`sionally severe desquamation, has been found to be!
`more common and more severe with docetaxel than
`with paditaxel. Skin biopsies have revealed a toxic der·
`malitis. Another troubling toxicity that has occurred in
`multiple trials is the development of a syndrome of fluid
`retention, which appears to be related to cumulative
`dose and often requires cessation of treatment after five
`to six cycles. Peripheral edema, pleural effusions, and/
`or weight gain occur in 80% of patients. It seems that
`capillary leakage is responsible for this syndrome, be(cid:173)
`cause cardiac and renal function remain undisturbed.
`Future studies will try to overcome this side effect by
`premedicating with corticosteroids or other membrane
`stabilizers.
`Preliminary results from five Phase II trials in breast
`cancer are shown in Table 4.3•·•0 Although fewer pa·
`ticnts have been treated in these studies, an overall re(cid:173)
`sponse rate of 54-76% has been noted. Particularly sig·
`nificant is the high response rate seen in metastatic vis·
`ceral sites, especially
`the
`liver. Thus, docetaxel
`possesses significant activity in breast cancer, and Phase
`
`II trials of docetaxel in combination with other active
`agents are being developed.
`
`Vinorelbine
`
`Two other microtubule interactive agents, vincristine
`and vinblastine, have been used in breast cancer regi·
`mens for many years. In contrast to the taxanes, these
`agents inhibit microtubule formation. Vinorelbine (Na(cid:173)
`velbine, Burroughs-Wellcome Co., Research Triangle
`Park, NC) is a new semisynthetic vinca alkaloid under
`development. It is the only vinca modified in the cath·
`aranthine ring rather than the vindoline ring of the mol·
`ecule.41 In addition to inducing cellular blockade at
`metaphase, vinorelbine is unique among the vincas in
`its ability to induce an earlier blockade at prophase."
`Vinorelbine had demonstrated substantial activity in
`both in vivo and in vitro NCI screens.43 It has proven to
`be active against all tumor models previously known
`to be sensitive to other vincas; however, these models
`demonstrated cross-resistance between vinorelbine and
`the other vincas.
`Similar to other vincas, vinorelbine is cleared pre·
`dominantly through the liver. It also is taken up actively
`by most tissues, resulting in a long half-life (mean of 40
`hours). Phase I trials have shown that the drug can be
`administered safely at an JV dose of 30 mg/m2 weekly,
`with the predominant toxicities limited to leukopenia,
`phlebitis, alopecia, constipation, and rare peripheral
`neuropathy.44
`The response rate of patients with advanced breast
`cancer to IV vinorelbine administe.red wl1ekly is shown
`in Table s.•s-s• Response rates range from 40% to 50%,
`with an overall 5% complete response rate. Patients
`with less prior treatment fare better than those who are
`more heavily pretreated, and complete responses do
`occur.
`Vinorelbine also has been combined with other ac·
`tive agents against breast cancer, such as epirubicin, mi(cid:173)
`55 Mean·
`toxantrone, S·fluorouracil, and doxorubicin.52
`•
`ingful complete responses (range, 20-33%) and overall
`response rates (66%) have been observed. Nonetheless,
`these trials are small, and confidence intervals for re·
`sponse certainly overlap those for many other active
`single agents. For navelbine to replace the existing vin·
`cas for breast cancer treatment, it will be necessary to
`prove its superiodty in Phase Ill trials of sufficient size
`to detect differences at the 5-10% level.56
`
`Anthrapyrazoles
`
`Anthracycline compounds have played a prominent
`role in the cytotoxic treatment of breast cancer. These
`cell cycle-specific agents have several postulated mech(cid:173)
`anisms of action, including DNA intercalation with sub·
`
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`CANCER Supplement A11g11st 1, 1994, Volume 74, No. 3
`
`Tab lo 4. Phase II Trials of Docctaxel in Advanced Breast Cancer
`No. o( responses
`lnslitution
`No.of
`(rdcrence
`cv.il u.J.ble
`No.I
`pilliCnt$
`
`Dose and
`schcduJc•
`
`EORTC,.
`NCIC"
`
`100 mg/m1
`IOOms/m1
`
`EORTC"
`
`IOOmg/m'
`
`MOA"
`
`100mg/m1
`
`24
`34
`
`33
`
`6
`
`MSKCC ..
`
`100mg/m'
`
`29
`
`Prior
`treatment
`
`CRC¥.I
`
`Mcts-24
`Adj-7
`
`2(8)
`3 (9)
`
`1>nw.1
`11 t (46)
`19 (SS)
`
`Ad}-12
`
`6 (18)
`
`18 (55)
`
`Adj-1
`Mcls-4
`Adj-NA
`
`(66)
`
`2(7)
`
`20 (69)
`
`Toxi<lly
`
`6/24 wilh l.ic skin re•clions
`53% nonprcmcdic•lcd p'1lien1s had HSRs, 25% hod
`febrile ncutropenla rC(luiring dose reductions
`74'lb removed from Sludy due 10 edema and/or
`effusion
`6/6 Cradc 2 skln reoclions
`
`24/29 develo~d edema, effusion or weigh! gain;
`28% dcvelo~d l ISl~s (non·premediatctl)
`Mets: m.:l.&'.Sliltk: Adj; ~diuv.ant; NA: not av.iil.ible; HSRs: hypcn.tnsltlv1ty rC\tCllon': CR: compltte rdpon~: Pl~: p.>rtl.il respon~ .
`.. All p.atl~nt1rtcclvtd1he doetl1Ut1;I do)t ovet 1 hour .ind hJ w.>s rcpc.itcd i:vtry 3 weeks.
`t 4of1hc 11 h.\d 1 l'R oot yn l.i.sting 4 w~ks .u bn'M.! uf this rqNrt.
`
`sequent topoisomcrase (topo)-II inhibition, and free
`radical generation, leading to oxidation or intracellular
`macromolccules.57 The latter effect has been implicated
`as a cause or the delayed, cumulative cardiotoxicity ob(cid:173)
`served with these compounds. In some cases, this can
`result in cardiomyopathy, irreversible congestive heart
`failure, and death. In addition, other commonly used
`drugs with similar mechanisms, doxorubicin and mitox(cid:173)
`antronc, are ineffective in cells possessing the MOR
`phenotype. This phcnomcn" is ;>s--.. ocfatcd with an ovcr(cid:173)
`expression of P-glycoprotein, which actively expels xe(cid:173)
`nobiotics (including anthracyclines) from the intracellu(cid:173)
`lar milieu. Therefore, recent efforts have centered on
`the development of analogs that have less cardiac tox(cid:173)
`icity or arc non-cross-resistant in MOR cells.
`Anthrapyrazoles are rationally designed anthracy(cid:173)
`dine analogs in which the quinone chromophore is
`made resistant to degradation to a semiquinone.'8 As
`the latter moiety has been implicated in the generation
`or the tissue-damaging free radicals, it is presumed that
`this modification will result in compounds that have
`
`less cardiac toxicity. Losoxantrone and piroxantrone are
`two anthrapyrazolcs that have been studied clinically.
`Uoth drugs have demonstrated activity against the MX-
`1 mammary carcinoma xenograft model employed in
`the NCl's drug screen as well as some degree of non(cid:173)
`cross resistance when tested against a doxorubicin re(cid:173)
`sistant 16C mammary carcinoma cell line.59 Phase a
`trials of these compounds have been conducted in
`women with breast cancer.
`Piroxantrone hn~ been tested, but with disappviut(cid:173)
`ing results.60 Thirty women who previously had re(cid:173)
`ceived 1 prior chemotherapy regimen were treated with
`160 mg/m1 every 3 weeks, with 6 patients. achieving
`a response (20%) with 1 having a complete response.
`Conversely, losoxantronc (50 mg/m1 every 21 days)
`showed promising activity when administered to 30
`evaluable women with advanced breast cancer.61 Equal
`response rates were observed in women previously
`treated with cytotoxics (10 o( 16 patients (63%)) and
`cytotoxic-nai've patients (9 of 14 patients (64%]), al(cid:173)
`though the only two complete responses were observed
`
`Table 5. Phase 11 Trials of Weekly Navelbine (30 mg/m') in Breast Cancer
`
`Author
`
`No.of
`evaJu:able
`p.Jtients
`
`PfiOr
`ch<molherapy
`for met.tstases
`(noJ
`
`24
`C•nobbio"
`Marty ..
`25
`Delozier"
`141
`Bruno"•
`44
`106
`Weber•~
`R•binovichw
`20
`Uuck"
`47
`Cit <0mpl<t• rnponst; PR: port .. 1 r~; NA: not .. •d•l>l<.
`• RflulH, repottf'd °"ly .u o\lnall fnpe>Mf'.
`t Rtsponsc dut•tiot\ rtponed only for p.ill<nts in Cit.
`
`5
`25
`0
`44
`41
`0
`0
`
`Response
`
`Cll('Y•)
`
`5(21)
`I (4)
`18 (13)
`3(7)
`II (JO)
`I (5)
`
`I'll ('Y<J
`
`6 (25)
`8(32)
`69(49)
`20(45)
`22(21)
`9(45)
`
`(SI)"
`
`Median duration
`(wkl (rong<l
`
`22 (9-41)
`NA
`
`42
`
`N/A
`38 (ll-47)t
`28
`
`NA
`
`10 of 18
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`1169
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`in the latter cohorl. Response duration was 37 weeks.
`Leukopenia was the dose-limiting toxicity, with no pa(cid:173)
`tient developing clinical evidence of cardiac toxicity.
`Other toxicities, such as nausea and vomiting, alopecia,
`and mucositis, were observed less frequently in these
`patients than in those treated with anthracyclines in
`earlier trials. Thus, with the data currently available, it
`appears that Iosoxantrone is the anthrapyrazole with
`the greatest clinical potential for treating breast cancer.
`
`Pyrazoloacridine
`
`Pyrazoloacridine is another DNA intercalator under de(cid:173)
`velopment with several unique features. Similar to dox(cid:173)
`orubicin, it induces DNA strand breaks, possibly
`through a topo-11 interaction,61 and inhibits RNA and
`DNA synthesis.0 It is being developed, in part, because
`of its in vitro and in vivo activity against solid tumor cell
`lines, including mammary carcinoma cells possessing
`the multi-drug resistance phenotype."' In addition, it
`has a favorable