Chapter 9 Oncology

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Chapter 9 Oncology

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CHAPTER 9 - Oncology
John M. Daly Monica Bertagnolli Jerome J. DeCosse Donald . Morton INTRODUCTION Approximately 90 percent of patients with malignancy un ergo surgical therapy for iagnosis! primary treatment! or management of complications" Resection is the initial curati#e treatment for a$out %& percent of patients! $ecause cancer is assume to $e a locali'e isease for an inter#al! allowing cure after a e(uate surgical remo#al" )ong* term sur#i#al statistics of patients with cancer treate surgically support this assumption" The lac+ of further impro#ement of sur#i#al rates with larger or more ra ical operations suggests that other forms of treatment shoul $e implemente to maximi'e cure rates" Inclusion of ra iation therapy or chemotherapy! or $oth! may impro#e the o#erall sur#i#al rate while permitting less extensi#e operati#e resection an enhancing cosmesis an function" The surgeon is responsi$le for the initial iagnosis an management of many types of cancer" ,nowle ge of tumor staging an the natural history of neoplastic isease is essential to a multimo al approach for treatment of the patient in colla$oration with the me ical oncologist an ra iotherapist" The surgeon-s gui ing principles shoul $e the accurate iagnosis an staging with a e(uate operati#e remo#al of locali'e isease .Ta$le 9*/0 an palliation of symptoms when possi$le" If the cancer has sprea $eyon local cure! the goal is to control the patient-s symptoms an to maintain maximum acti#ity as long as possi$le" The success of palliati#e therapy is measure in terms of useful life" The most common criterion of incura$ility is istant metastasis" 1owe#er! patients with solitary pulmonary metastases may $e cura$le $y resection! an those with wi esprea metastases from choriocarcinoma may $e cura$le with chemotherapy" )ocal extension also may $e a criterion of incura$ility" If extensi#e stu ies fail to emonstrate metastatic isease or incura$le local extension! the patient-s treatment shoul $e irecte towar a cure" 2anagement of the cancer patient is a multi isciplinary effort re(uiring colla$oration among surgical oncologists! ra iation oncologists! me ical oncologists! reconstructi#e surgeons! an other oncologist specialists" 3#i ence suggests that com$inations of surgery! ra iation therapy! chemotherapy! hormone therapy! an immunotherapy significantly impro#e cure rates a$o#e those achie#e with any single therapeutic mo ality" 2ultimo al therapy! for example! is stan ar for most $reast an colon cancer patients .4ig" 9*/0" As the primary coor inator in cancer management! the surgeon must fully un erstan the in ications! ris+s! an $enefits of surgery! a 5u#ant chemotherapy! hormonal therapy! ra iation therapy! an the importance of reconstructi#e surgery" The optimal com$ination an se(uence of treatments is etermine $y the patient-s physical! emotional! psychological! an reha$ilitati#e nee s" The patient-s general con ition an the presence of any coexisting isease must $e consi ere " 6urgery may $e contrain icate in a patient who has recently experience a myocar ial infarction" A patient with preexisting ia$etes will $e more suscepti$le to the toxic effects of

hormonal therapy with corticosteroi s" Renal isease can increase the toxicity of some of the chemotherapeutic agents! such as methotrexate" Any e#i ence of infection or $lee ing may re(uire #igorous treatment $efore efiniti#e therapy is initiate " The patient-s psychologic ma+eup an family! frien ! an 5o$ support structure must $e consi ere " A patient who is una$le to accept the realities of a gi#en treatment shoul $e offere an alternati#e approach if possi$le" This is particularly true of surgical proce ures that significantly alter appearance or in#ol#e change of organ function re(uiring the patient-s aily care! such as colostomy" 3xperimental forms of therapy! such as intraarterial infusion of rugs! shoul also $e a#oi e in some patients7 a patient who is unwilling to tolerate the incon#enience of an intraarterial catheter might remo#e it without me ical appro#al" Determining a treatment plan re(uires the integration of information from four areas8 ./0 natural history of the isease $y histologic type! .90 clinical staging! .:0 goals of specific treatments! an .;0 in ications an ris+s for each treatment .or com$ination of treatments0 $ase on results of experience an clinical trials" 3<ID32IO)O=> Cancer is o#erta+ing heart isease as the most fre(uent cause of eath in the Unite 6tates! accounting for 9; percent .approximately &90!0000 of eaths each year" The fi#e lea ing causes of cancer eath among males in the Unite 6tates are8 lung! :9 percent7 prostate! /; percent7 colon an rectum! 9 percent7 leu+emia an lymphoma! 9 percent7 an pancreas! & percent .4ig" 9*90" Among females the lea ing causes of cancer eaths are8 lung! 9& percent7 $reast! /% percent7 colon an rectum! /0 percent7 leu+emia an lymphoma! ? percent7 an o#ary! @ percent .4ig" 9*:0" <rostate cancer is the most fre(uent life*threatening cancer in men! an $reast cancer the most fre(uent in women" The impact of cancer is no less on a worl wi e $asis7 hepatocellular cancer is the cause of approximately / million eaths a year" Although neoplasia is a isease of the genome with many common molecular pathways! human cancer may $e en#isione as more than /00 istinct entities! each efine $y the cell or tissue of origin an the appearance un er the microscope" 4or some! the initial in ucti#e e#ent is inherite ! $ut! as emonstrate $y ,nu son! general $elief is that more than one genetic or epigenetic e#ent is necessary for promotion of human carcinogenesis" 3ach site has a host*tumor interface an a su$clinical growth phase! which might $e measure in eca es $efore emerging at a clinical threshol " At a threshol le#el! almost all common sites of life* threatening cancer ha#e a efina$le $enign precursor .Ta$le 9*90 that shares the epi emiology of the life*threatening tumor an that may $e re#ersi$le" 6creening policies for the pre#ention an early etection of cancer emerge from un erstan ing the natural history of cancer at specific sites" The hallmar+ of an effecti#e screening policy is emonstration of a re uce mortality rate" This goal has $een achie#e $y the <ap smear for cer#ical cancer! mammography for $reast cancer! an the fecal occult $loo test an sigmoi oscopy for colorectal cancer" To a large extent our present +nowle ge a$out the etiology an control of cancer has emerge from epi emiology" O$ser#ational ecological stu ies! international correlations among populations an migrants! an cross* sectional sur#eys! reinforce $y case*control an cohort stu ies! ha#e $een the $asis for conclusions a$out etiology"

Ne#ertheless! when all +nown causes are accounte for! the o ac(uiring cancer still epen su$stantially on chance"

s of a person-s

The primary eterminants of ris+ ha#e $een inci ence rates an mortality rates! the former efine $y the num$er of new e#ents or cases that e#elop in a population of in i#i uals at ris+ uring a specific inter#al" These rates shoul $e istinguishe from pre#alence .the num$er of affecte persons within a population0" Rates can $e cru e! category*specific .e"g"! age! gen er! or race0! or a 5uste .e"g"! accounting for mortality from other causes0" 1erein resi es the #alue of population*$ase registries an of high*ris+ registries in which persons at ris+ can $e concentrate for stu y an treatment" )ong*term changes in cancer inci ence an mortality in the Unite 6tates .see 4igs" 9* 9 an 9*:0 efy a satisfactory explanation! $ut an aging population an some inter#entions are partial explanations" In the Unite 6tates! a nota$le ecrease in the inci ence an mortality of gastric cancer has occurre o#er the past half century! presuma$ly as a result of general pu$lic health measures an ! possi$ly! refrigeration! $ut without a specific un erstan ing or inter#ention" 4or many eca es $reast cancer inci ence has $een increasing while mortality has remaine sta$le! $ut now there is a ecline in mortality! a result of wi esprea acceptance of mammography an etection of $reast cancer in an earlier! cura$le stage" In recent years the mortality rate of lung cancer has sta$ili'e in men! an effect attri$uta$le to re uction in cigarette smo+ing" 4rom glo$al stu ies $y Doll an <eto! #astly ifferent inci ence rates of site*specific cancer ha#e $een foun .Ta$le 9*:0" Cancer of the stomach remains a lea ing cause of eath in Asia an eastern 3urope" Ahen nati#es of Bapan! where gastric cancer is fre(uent an colorectal cancer uncommon! emigrate to 1awaii! o#er one generation the fre(uency of these cancers was re#erse ! a change attri$ute to a option of the Aestern iet" =i#en that iet an nutrition may $e characteri'e as an en#ironmental factor! these ifferences incriminate en#ironment*in uce molecular e#ents in human carcinogenesis" The more fre(uent occurrence of cancer in ol er persons may reflect accumulation of en#ironmentally $ase genetic e#ents as well as molecular e#ents associate with senescence" Ac(uire genetic or epigenetic e#ents originating in physical! chemical! an #iral etiologies are escri$e in more etail $elow7 initial insights were eri#e from o$ser#ational stu ies" The increase inci ence of colorectal cancer in the Unite 6tates can $e attri$ute to the high fat an meat content of the Aestern iet" 2eta$olic epi emiology encompasses other effects of the internal en#ironment on carcinogenesis as well" 4or example! $reast cancer in women can $e relate to the lifetime uration of unprotecte exposure to $iologically acti#e estrogens" 3arly menarche! late menopause! an elaye or a$sent chil * $earing increase ris+! whereas oophorectomy an estrogen antagonists re uce ris+" Recognition of internal an external en#ironmental interactions in human carcinogenesis pro#i es the means for ris+ re uction an the e#elopment of pre#ention strategies" 3limination of exposure to as$estos or ra iation! a#oi ance of occupational carcinogens! an re uction of cigarette smo+ing remo#e certain carcinogens from the en#ironment an re uce ris+" 6unscreens $loc+ the carcinogenic

wa#elength of ultra#iolet light" Caccination for hepatitis D #irus re uces the ris+ of hepatocellular cancer" Other measures to control en#ironmental carcinogens may $e irecte to the internal en#ironment $y nutritional mo ification an chemopre#ention" A low*fat! high*fi$er iet re uces ris+ of colorectal cancer an ! possi$ly! $reast an prostate cancer" Oral #itamin A analogues re uce leu+opla+ia an secon cancers in the aero igesti#e epithelium" Oral nonsteroi al anti* inflammatory rugs ecrease rectal a enomas in patients with familial a enomatous polyposis" Antiestrogens re uce secon cancers in the $reast" DIO)O=> O4 2A)I=NANT TRAN64OR2ATION 1istory Cancer has $een recogni'e as a isease for thousan s of years" The first +nown mention of cancer is in the 3$ers <apyrus! a me ical treatise written in 3gypt a$out /@00 $"c" The manuscript recommen s surgical excision or cauteri'ation for tumors" The scientific a #ances of the =ree+s an Romans le to the un erstan ing that cancer results from physiological processes" =alen .a" " /99Eca" /990 efine cancer as Ftumors against natureG an ascri$e the cause of cancer to FhumoralG im$alances" <aracelsus .a" " /;9:E/&&/0 argue that cancers were cause $y external agentsH which is supporte $y current literature lin+ing cancer e#elopment to en#ironmental carcinogens" It was not until the /?&0s that Ru olf Circhow! the father of cellular pathology! recogni'e cancer as an alteration of the nati#e tissues" In the /?%0s Bulius Cohnheim argue that cancer was a failure of em$ryonic cells present in all tissues to mature properly! the first mention of carcinogenesis as F e ifferentiation"G Theo or Do#eri! a professor of 'oology at the Uni#ersity of AIr'$urg in =ermany! reporte in /909 that his stu ies of mitosis in sea urchins le him to $elie#e that cancer was ue to a$normal chromosomes" Do#eri-s theory compete with the infectious isease theory of carcinogenesis! $ut the i entification of the chic+en leu+emia #irus $y 3llerman an Dang in /90? an Rous-s i entification of the chic+en sarcoma #irus in /9// $rought the infectious isease theory $ac+ to the forefront" ,nu sen! in his /9%/ escription of familial retino$lastoma! suggeste that a com$ination of inherite an ac(uire e#ents go#ern cancer e#elopment" 2ore recently Cogelstein an e la Chapelle! on the $asis of their i entification of an association $etween cancer an inherite efects in DNA repair! postulate that epithelial cancers result from a failure of the cell to maintain DNA fi elity uring replication" The common enominator in all theories of carcinogenesis is alteration of the cell-s genome! either $y irect amage from ra iation or chemicals! $y integration of #iral genomic se(uences! or $y an inherite efect in DNA repair capacity" The stu y of cancer etiology is focuse on the molecular e#ents re(uire for malignant transformation! particularly the interplay $etween genetic an en#ironmental influences in carcinogenesis" Cellular 1omeostasis It is instructi#e to stu y normal regulatory processes to un erstan the erangements that occur with carcinogenesis" To achie#e homeostasis in tissues! renewa$le cell populations must perform four relate functions7 they must ./0 proliferate with proper timing an fi elity of DNA content! .90 ifferentiate in a pattern consistent with normal function of the tissue! .:0 in#olute in a manner such that the proliferation an

in#olution rates are $alance ! an .;0 repair any amages to their DNA resulting from exposure to mutagens such as ra iation! toxins! an transforming #iruses .4ig" 9*;0" A efect in any of these functions can result in tumor formation" Carcinogenesis The term cancer refers to a group of iseases characteri'e $y the autonomous growth of a$normal! FneoplasticG cells" Cancer results from a eregulation of critical aspects of cellular function! such as proliferation! ifferentiation! an apoptosis" Aithout the proper constraints on these processes! neoplastic cells repro uce in great num$ers! in#a e a 5acent structures! an e#elop metastatic colonies" The natural history of most cancers suggests that the e#elopment of these a$normal characteristics occurs in a progressi#e fashion" In escri$ing this process! tumor initiation is efine as the exposure of cells to agents that in uce an inherita$le genetic change! i"e"! agents that are genotoxic or in uce critical mutations $y $in ing of electrophilic carcinogenic meta$olites to DNA" Tumor promotion is the exposure of initiate cells to agents that in uce their proliferation" This proliferation may allow other spontaneous mutations to occur that culminate in expression of malignant phenotype .malignant transformation0" Tumor progression escri$es successi#e e#elopment of increase local growth! in#asion! an metastasis $y transforme cells" Cancer <henotype <rogression of a tissue to malignancy istur$s host homeostatic mechanisms! as characteri'e $y ./0 unresponsi#eness to normal growth regulators! .90 in#asi#e phenotype! an .:0 e#asion of immune*me iate tumor estruction" Tumors are thought to $e clonal in origin .i"e"! all of the cells within a tumor arise from a single progenitor cell whose growth regulation has $ecome erange 0" 6upport for this clonal theory comes from the o$ser#ation that tumors arising in women who are hetero'ygous for a gene enco ing the en'yme glucose*@*phosphate ehy rogenase .=@<D0 express only one of the two isoen'ymes" In a ition! all of the neoplastic cells in patients with chronic myelogenous leu+emia whose tumor $ears the <hila elphia chromosome .<h/0 contain <h/" 6ome ata from animal mo els! such as chemically in uce murine fi$rosarcoma! suggest that soli tumors may $e multicellular in origin" Clonal ominance! howe#er! has $een emonstrate for $oth murine an human tumors" Despite their possi$le clonal origin! cancers! particularly the soli tumors! are heterogeneous in character" A cancer mass inclu es tumor cells an their supporting $loo #essels an stroma" Aithin the tumor! a$normal regulation of cellular function lea s to nuclear an cellular polymorphism! loss of cellular polarity! an #ariation in DNA content from cell to cell .aneuploi y0" These processes are accelerate as cells lose control o#er DNA repair" As regions of tumor outstrip their $loo supply! areas of inflammation an necrosis further contri$ute to tumor heterogeneity" As a result of loss of the fi elity of DNA replication! changes in the malignant cell population occur throughout the course of tumor progression" This is $est emonstrate $y a change in ifferentiation state or tumor antigen expression $etween primary tumors an their metastatic foci" In an i eali'e mo el! the growth of a tumor procee s exponentially in the early phases when the supporting tissues an nutrients are optimal! with a shortening of the ou$ling time as the tumor enlarges" This relationship $etween time an tumor si'e is referre to as =ompert'ian growth! name for the eighteenth*century mathematician

Den5amin =ompert'! who e#elope the mo el that escri$es it" The natural history of many human tumors is escri$e $y this mo el .4igs" 9*& an 9*@0" <rogression of a tissue to malignancy in#ol#es se#eral stages" The earliest #isi$le e#i ence of neoplastic transformation is ysplasia! a con ition in which epithelial tissues exhi$it altere si'e! shape! an organi'ation" Dysplasia is a common reaction of tissue to chronic inflammation or exposure to en#ironmental toxins or irritants" The egree of e#iation from normal cellular an tissue architecture efines ysplasia as mil ! mo erate! or se#ere" In epithelial tumors! ysplastic cells are confine to the region a$o#e the $asement mem$rane" Decause ysplastic cells retain a measure of control o#er cellular proliferation! ysplasia is generally re#ersi$le once the inciting factor is remo#e " In most tissues! howe#er! se#ere ysplasia is associate with progression to carcinoma if left without inter#ention" The hallmar+ of a soli tumor carcinoma is the a$ility to in#a e the $asement mem$rane an sprea without regar to normal tissue $oun aries" )ocal isease is the term use to refer to in#asi#e tumor that is confine to the tissue of origin" Once the $asement mem$rane has $een $reache ! the next $arrier to tumor issemination is the networ+ of raining lymph no es" Tumor sprea to the lymph no es raining the tissue of origin is terme regional isease" The final stage of tumor progression is metastasis! where$y in epen ent colonies of tumor are esta$lishe in istant sites fa#ora$le to tumor growth" This type of tumor is commonly referre to as istant isease" Carcinogens In /%%& 6ir <erci#al <otts! a surgeon at 6t" Dartholomew-s 1ospital in )on on! escri$e the Fsoot wart!G a s(uamous cell carcinoma of the scrotum in chimney sweeps" This was the first recognition that cancer is a isease relate to long*term exposure to associate en#ironmental factors" 2olecular stu ies lin+ some +nown carcinogens to specific cancer*associate mutations! e"g"! $en'oJaKpyrene! a component of cigarette smo+e! is a potent mutagen that preferentially in uces amage of the p&: tumor suppressor gene at nucleoti es that are common mutation sites in human lung cancer" 3n#ironmental factors implicate in carcinogenesis inclu e ra iation! chemical agents! an #iruses" The common enominator among these factors is the a$ility to in uce herita$le change in cellular DNA" <hysical Carcinogens Tumor in uction $y physical agents occurs $y essentially two mechanisms8 ./0 in uction of cell proliferation o#er an exten e perio of time! which increases the opportunity for e#ents lea ing to transformation7 an .90 exposure to physical agents that in uce amage or changes in cellular DNA" 4oreign $o ies! particularly irritants! can in uce tumors in animal mo els7 howe#er! it is ifficult in humans to attri$ute the in uction of a tumor solely to the presence of a foreign $o y" 4oreign $o ies may act as cocarcinogens or promoters! or may pro uce a chronic irritation that exposes tissue to carcinogenesis $y other en#ironmental agents" The higher ris+ of s+in cancer in patients with $urns or esophageal cancer after chemically in uce irritations! such as that following lye ingestion! pro#i es an example of the close lin+ $etween tumorigenesis an the in uction of cell proliferation" Cellular proliferation associate with chronic inflammatory con itions may contri$ute to the carcinogenicity of other agents or may increase the pro$a$ility of genetic changes resulting in neoplastic

transformation" An example is the increase colorectal cancer ris+ in inflammatory $owel isease" The $est +nown agent of physical carcinogenesis is ra iation" There are two types of ra iation8 ioni'ing an non*ioni'ing" Ioni'ing ra iation inclu es x* rays an gamma rays! an alpha an $eta particles! while the most common form of non*ioni'ing ra iation is ultra#iolet .UC0 ra iation" Doth types of ra iation are associate with human cancers! $ut the two groups in uce ifferent types of tumor" Ioni'ing Ra iation Ahen a ministere in high oses! all forms of ioni'ing ra iation in uce tumors" The carcinogenic potential of x*rays was reporte $y 4rie$en in /909! soon after they were isco#ere ! when many ra iologists ha e#elope s+in cancers" 4rom /9/: to /99; a ra ium*$ase paint was use to illuminate watch ials! an more than a thousan wor+ers in a New Bersey plant were expose to this alpha*particle emitter" Dy /9:/ unusually high rates of aplastic anemia an osteosarcoma among ra ium wor+ers were note ! alerting scientists to the carcinogenic potential of alpha particle exposure" 6ur#i#ors of the nuclear $om$s roppe on Bapan in /9;& ha#e an increase inci ence of chronic myeloi leu+emia an carcinomas of the lung! thyroi ! an $reast! with a /0* to 90*year latency $efore e#elopment of isease" The results of ra iation exposure are ose an time relate " The carcinogenic effect of ioni'ing ra iation is through in uction of $rea+s in DNA stran s" Cells most suscepti$le to this amage are those with a high mitotic acti#ity! such as hematopoietic an epithelial tissues" A population with increase sensiti#ity to ioni'ing ra iation an other DNA* amaging agents has $een i entifie among in i#i uals hetero'ygous for a gene mutation responsi$le for the recessi#e isor er ataxia telangiectasia .AT0" Approximately 9 percent of the population are hetero'ygous carriers of a efecti#e AT gene allele an emonstrate a four*fol increase in cancer inci ence! inclu ing tumors of the stomach! $reast! s+in! o#ary! $rain! an hematopoietic cells" It is postulate that these in i#i uals lac+ the a$ility to repair DNA! although the specific efect associate with AT gene mutation is un+nown" An un erstan ing of the amage cause $y ioni'ing ra iation! the tissue penetration of ifferent agents! an the a #ent of mo ern osimetry ha#e re uce the cancer ris+ associate with therapeutic ra iation" Ra iation therapy for con itions such as 1o g+in-s lymphoma an $reast cancer still carries a ris+ of treatment*relate ! secon malignancies such as leu+emia or soft tissue sarcoma" Non*ioni'ing Ra iation The association $etween s+in cancer an ultra#iolet light was first o$ser#e in murine experiments $y 1y e in /90@" UC light may $e responsi$le for the in uction or promotion of a num$er of human s+in tumors! inclu ing $asal cell carcinoma! s(uamous carcinoma! an malignant melanoma" UC ra iation is a$sor$e $y DNA an in uces DNA amage! particularly the formation of thymi ine imers" DNA repair en'ymes that are functioning normally are a$le to repair these efects" In i#i uals with xero erma pigmentosa ha#e a efecti#e en onuclease an are una$le to incise the stran s amage $y UC exposure" Decause UC*in uce errors go unrepaire in these in i#i uals! they e#elop multiple s+in cancers" 2elanin has a

protecti#e effect in a$sor$ing UC ra iation! an therefore fair*s+inne in i#i uals are at greatest cancer ris+" Cancer*associate DNA amage may also result from physical factors such as the foreign*$o y reactions in uce $y as$estos or through reacti#e oxygen species li$erate at sites of chronic inflammation" 3xposure to ra iation may in uce immunosuppression! contri$uting to carcinogenesis $y a lac+ of immune sur#eillance" Clinical an experimental mo els suggest that physical irritants! such as as$estos! may act as cocarcinogens7 thus! for example! a com$ination of as$estos exposure an cigarette use may $e synergistic in pro ucing mesotheliomas! lung cancer! an associate epithelial tumors" O$ser#ations such as these suggest that in the multistage process of carcinogenesis! physical agents may fulfill one or more of the critical steps necessary to in uce a tumor" Chemical Carcinogens The first report of a chemical agent in ucing cancer was 1ill-s escription in /%@/ of nasal carcinoma associate with the use of snuff" The correlation $etween cigarette smo+ing an lung cancer was emonstrate $y Doll an 1ill in /9&0! an to$acco pro ucts remain the source of most chemically in uce human cancers" 3pi emiologic stu ies re#eal that a su$stantial num$er of compoun s are associate with chemical carcinogenesis" )i+e to$acco smo+e! most presume carcinogenic su$stances are a complex mixture of chemicals! rather than a single! pure agent" In a ition! a num$er of +nown chemical carcinogens re(uire meta$olism from a procarcinogen into carcinogenic reacti#e electrophilic interme iates that alter cellular DNA" DNA amage $y carcinogen meta$olism epen s on the $alance $etween the rate of oxi ation to carcinogenic interme iates an the rate of etoxification of these oxi ati#e pro ucts #ia con5ugation with glutathione an glucuronic aci " There are se#eral main classes of chemical carcinogens! inclu ing organic an inorganic su$stances" <olycyclic hy rocar$ons are organic carcinogens that un ergo meta$olism in the host to an acti#e form" The most extensi#ely stu ie polycyclic hy rocar$on is $en'oJaKpyrene! a component of cigarette smo+e! fossil fuel com$ustion pro ucts! an smo+e foo s" The meta$olic pro ucts of $en'oJaKpyrene an relate compoun s are electrophilic epoxi es that $in to intracellular proteins! such as DNA" Den'oJaKpyrene is con#erte to its toxic meta$olites through the action of the hepatic en'ymes cyclooxygenase an cytochrome <*;&0 .4ig" 9*%0" Aromatic amines! such as $*naphthylamine! $en'i ine! aminofluorenes! an imethylaminoa'o$en'ene .DAD0! also un ergo meta$olic con#ersion to acti#e forms an are associate with tumors of the urinary tract an li#er" Inorganic carcinogens inclu e hea#y metal pro ucts of fossil fuel com$ustion such as nic+el! ca mium! chromium! arsenic! an lea " 2etal carcinogens are mutagenic! in ucing DNA a ucts an DNA cross*lin+ing" Chronic occupational exposure to these carcinogens is associate with a num$er of tumors! e"g"! nasopharyngeal carcinomas su$se(uent to chronic exposure to nic+el*smelting pro ucts" Ciral Carcinogens Ciruses are pac+ages of genetic information! in the form of either DNA or RNA! protecte $y a structural protein coat" Ciruses may insert their genetic material into host cells an in uce changes morphologically consistent with neoplastic transformation .4ig" 9*?0" 2uch of our present un erstan ing of carcinogenesis is

eri#e from the stu y of the effects of #iral mo ification of cellular function" RNA retro#iruses isolate from chic+en sarcomas emonstrate that sarcomas coul $e transmitte $etween chic+ens $y a cell*free infiltrate" It is now recogni'e that $oth RNA an DNA #iruses are capa$le of in ucing tumors in humans! although only a small proportion of in i#i uals infecte with a cancer*associate #irus e#elop tumors" Cirus*associate cancers arise after an incu$ation perio of years to eca es! suggesting that other genetic or en#ironmental factors contri$ute to #irally in uce carcinogenesis" O$ser#ation of the effect of oncogenic #iruses on cellular homeostasis suggests that the ifferent oncogenic #iruses use similar strategies to eregulate cell growth" 2any of the oncogenic #iruses enco e proteins that interact with the same intracellular targets! particularly R$ an p&: proteins" The contri$ution of oncogenic #iruses to carcinogenesis may lie in the inacti#ation of these proteins that are essential for regulation of the cell cycle" The most common tumor #iruses are liste in Ta$le 9*;" DNA Tumor Ciruses 2ost of the human #irus*associate tumors are the result of infection with DNA tumor #iruses" Decause of the worl wi e pre#alence of hepatitis D* associate hepatocellular carcinoma! DNA tumor #iruses may $e the most common inciting factor for malignancy" 3pstein*Darr Cirus .3DC0 The pre#alence of 3DC infection worl wi e is extremely high! with seropositi#ity for 3DC anti$o ies approximately 90 percent" 3DC infects epithelial cells an some D cells an pro uces a spectrum of isease from acti#e! highly symptomatic forms such as acute infectious mononucleosis! to a chronic! in olent manifestation" Cancers e#elop in a small su$set of patients infecte with 3DC! an the epi emiology of these cancers suggests that cofactors in the en#ironment or genetic ma+eup of affecte in i#i uals are important for 3DC*in uce carcinogenesis" 4or example! Dur+itt-s lymphoma is almost entirely restricte to e(uatorial Africa! where malaria may $e a cofactor" In the Unite 6tates! extrano al 3DC*associate D cell lymphomas occur in the setting of immunosuppression after transplantation or in in i#i uals with ac(uire immuno eficiency syn rome .AID60" 1epatitis D Cirus .1DC0 Infection with hepatitis D #irus is common worl wi e" One of the many manifestations of hepatitis D is a chronic hepatic infection which ranges in se#erity from a mil ! essentially asymptomatic form! to se#ere! chronic! acti#e isease resulting in cirrhosis" Cohort an case control stu ies in 6outheast Asia an Africa suggest that 1DC infection is associate with the e#elopment of hepatocellular carcinoma" The 1DC transforming agent may $e the 1DC L gene! a segment of the 1DC genome that is consistently foun in 1DC*associate hepatocellular cancers" 1uman <apilloma#irus .1<C0 The in ication that s(uamous cell carcinoma of the cer#ix was associate with an infectious agent first came from epi emiologic ata showing an increase inci ence of this cancer in women with multiple sexual partners" O#er 90 percent of cer#ical carcinomas contain 1<C DNA! pre ominantly su$types /@ an /?! which is

integrate into the cellular DNA" 1<C #irus infects epithelial cells an in uces their proliferation" In the setting of epi ermo ysplasia #erruciformis! an autosomal recessi#e con ition associate with impaire cellular immunity! 1<C infection results in s(uamous cell carcinoma" The significant inci ence of s(uamous cell carcinoma of the anus o$ser#e in homosexual males is also ascri$e to the com$ination of 1IC* in uce immunosuppression an 1<C infection" RNA Tumor Ciruses In /9:@ Dittner reporte that an agent transmissi$le through mil+ was responsi$le for increasing the inci ence of $reast cancer in mice! resulting in the i entification of the mouse mammary tumor #irus" 6ince then! many other RNA #iruses ha#e $een associate with tumors in animals" RNA tumor #iruses are retro#iruses! a class of #iruses efine $y the presence of an en'yme calle re#erse transcriptase" Using re#erse transcriptase! the retro#irus pro uces a DNA copy of the #iral RNA genome that can $e integrate into the host cell DNA! lea ing to transformation" In human $eings! the T cell leu+emia #iruses 1T)C*I an 1T)C*II are cancer* associate RNA #iruses" )i+e 1IC! these #iruses specifically target CD;M T lymphocytes! contri$ute to immunosuppression! an in uce tumors of hematogenous origin" Immuno eficiency an Cancer The theory of immunological sur#eillance against cancer is that immune effector cells can eliminate cells that un ergo malignant transformation" Accor ing to this theory! the e#elopment of a tumor is a failure of immune sur#eillance in maintaining tissue homeostasis" Despite a #ances in the un erstan ing of carcinogenesis! the nature of immune sur#eillance an the role of the immune response cells in the progression of malignancy is unclear" 6tates of immunosuppression are associate with an increase ris+ of cancer" <atients recei#ing long*term immunosuppressi#e me ication for pre#ention of allograft re5ection ha#e an increase inci ence of s+in cancers an lymphoi malignancies" The carcinogenic effect of ioni'ing an non* ioni'ing ra iation may $e ue in part to ra iation*relate immunosuppression" =amma rays an x*rays irectly an in irectly affect the #ia$ility an function of lymphocytes" UC light in uces immunosuppression in irectly! possi$ly through release of $iologically acti#e su$stances from cells in the s+in" The coinci ence of #irally in uce tumor formation an states of immunosuppression pro#i es strong e#i ence that a normally functioning immune system acts to suppress carcinogenesis" 4or example! AID6 is associate with ,aposi-s sarcoma! non*1o g+in-s lymphomas! an s(uamous cell carcinomas" AID6* associate ,aposi-s sarcoma an non*1o g+in-s lymphomas commonly carry fragments of the ,aposi-s sarcoma*associate herpes*li+e #irus .,61C0 genome! while AID6*relate s(uamous cell cancers are 1<C* in uce " In experiments with carcinogen*in uce murine tumors! loss of T lymphocytes oes not significantly affect carcinogenesis $ut oes iminish host response to transplanta$le tumors" Analysis of the immune cell participants in the sur#eillance against neoplastic progression re#eals that in the normal host! se#eral lymphoi cell compartments! inclu ing T! D! an N, lymphocytes! as well as macrophages! participate in the pre#ention an estruction of a$errant cells" =enetic Alterations

The 2ultistep 1ypothesis Cancer is fun amentally an alteration in the genes that control cellular function" It is clear that the e#elopment of a malignant phenotype is multifactorial" 6ome a$normal genes .terme cancer suscepti$ility genes0 can $e inherite at conception as germline efects" The +nown cancer suscepti$ility genes affect the cell-s a$ility to etect an repair genetic amage! alter immune sur#eillance for tumors! mo ify cellular meta$olism of carcinogens! or regulate the growth of specific cell types" Other genetic changes! +nown as somatic mutations! are ac(uire through interaction with agents that alter the cellular genome! such as ra iation! mutagenic chemicals! or #iruses" Although the exact com$ination of genetic changes re(uire for carcinogenesis is not fully un erstoo ! e#i ence suggests that carcinogenesis re(uires the successi#e accumulation of genetic efects that result in the altere cellular growth an ifferentiation characteristic of a malignant phenotype" The genetic changes implicate in this Fmultistep hypothesisG of cancer e#elopment are $est un erstoo for colorectal cancer .4ig" 9*90" In /9?? Cogelstein an associates pu$lishe a report escri$ing specific mutations in colorectal cancer an efine their relationship to the a enoma*carcinoma se(uence" This report le to wi e acceptance of the multi*step hypothesis as the $asis for malignant transformation an ga#e a genetic perspecti#e to the processes of tumor initiation! promotion! an progression" Data suggest that not only are specific mutations essential for carcinogenesis! $ut also the or er in which these efects are ac(uire is important" Although the se(uence of e#ents is not completely un erstoo ! the multistep hypothesis gi#es us a useful framewor+ for efining the genetic nature of carcinogenesis" Oncogenes Oncogenes are genes that promote the transformation of normal cells into tumor cells! generally $y acti#ating growth*enhancing intracellular signaling pathways" Oncogenes can $e foun within mammalian cellular DNA .cellular oncogenes0 an in #iruses .#iral oncogenes0" Oncogenes are esignate $y three*letter names! which are usually eri#e from the tumors or the cell line in which the oncogene was first i entifie " 4or example! the first i entifie RNA #irus! the Rous sarcoma #irus! contains the src oncogene" Oncogenes eri#e from #iral genomes are la$ele with the prefix F#G .e"g"! #*src07 cellular oncogenes are la$ele with FcG .e"g" c*src0" <roto* oncogenes are normal components of the genome that function as oncogenes when altere or inappropriately expresse through processes such as chromosome rearrangement or #iral transformation" Oncogenes enco e proteins! sometimes terme oncoproteins! that alter cell cycle regulation! resulting in tumor formation" The isco#ery of RNA retro#iruses in the early twentieth century pro#i e the foun ation for our un erstan ing of oncogenes an their precursors! proto*oncogenes" After infection! retro#iral RNA is transcri$e into ou$le* stran e DNA $y the #iral en'yme re#erse transcriptase" The retro#iral DNA then is integrate into the chromosomal DNA of the host! forming a DNA pro#irus" The #iral DNA is transcri$e an translate $y host cell machinery into #iral RNA an #iral proteins! which are assem$le within the host cell" The new #irus particles are release from the host cell $y $u ing from the plasma mem$rane" Oncogenic #iruses contain genetic segments that lea ! on integration into the host genome! to neoplastic transformation of the host cell" Retro#iruses also can in uce tumors $y acti#ating host cellular proto*oncogenes" 4or example! the src gene enco es a mem$rane* associate en'yme responsi$le for phosphorylation of cellular proteins! an #iral transformation

through alteration of this gene results in a$normal intracellular signaling that contri$utes to tumor e#elopment" 3arly genetic stu ies showe that tumors contain many chromosomal a$normalities! inclu ing gain or loss of chromosomes .aneuploi y0! or alterations in in i#i ual chromosomes! such as translocations or amplifications" The role of the <hila elphia chromosome in human chronic myelogenous leu+emia is an example of oncogene acti#ation through chromosomal rearrangement" In the <hila elphia chromosome! a segment of chromosome 9! carrying the cellular oncogene c*a$l! is attache to chromosome 99! within a gene +nown as $cr" The expression of the resulting $cr*a$l fusion protein is important in the e#elopment of leu+emia! an o$ser#ation confirme in animal stu ies showing that intro uction of en ogenous $cr*a$l se(uences causes leu+emia .4ig" 9*/00" Oncogenes are i#i e into categories epen ing upon the role their proteins play in cellular function" These inclu e growth factors! growth factor receptors! cytoplasmic protein +inases! guanosine triphosphate .=T<0*$in ing proteins! nuclear transcription factors! an cell cycle regulators .Ta$le 9*&0" Tumor 6uppressor =enes an the Inherite Cancer <re isposition 6yn romes The normal effect of tumor suppressor genes is to +eep cellular growth in chec+" The loss of function of these genes lea s to tumor formation .Ta$le 9*@0" The classic example of a tumor suppressor gene is the retino$lastoma gene .RD/0" 3ach normal cell has two copies of the RD/ gene! an loss of RD/ gene function re(uires mutation of $oth copies" In familial retino$lastoma! affecte in i#i uals inherit one efunctionali'ing germline mutation in RD/ .4ig" 9*//0" 3xpression of the RD/ mutation phenotype re(uires loss of the secon allele $y somatic mutation! a concept +nown as ,nu son-s Ftwo*hitG hypothesis after ,nu son-s escription of familial retino$lastoma in /9%/" 2ost of the inherite cancer pre isposition syn romes escri$e to ate in#ol#e inheritance of one mutant an one normal allele of a tumor suppressor gene" Analysis of tumors arising in in i#i uals with germline mutations in tumor suppressor genes suggests that a itional mutations! such as in the oncogenes ras! c*myc! etc"! are re(uire for expression of the cancer phenotype! an o$ser#ation in +eeping with the multi*step hypothesis of carcinogenesis" This theory is further supporte $y #aria$ility in phenotypic expression an in time to e#elopment of cancer among the mem$ers of these families" It is pro$a$le that mo ifier genes or en#ironmental influences contri$ute to this #aria$ility" 1ere itary Retino$lastoma an the RD/ =ene Retino$lastoma! a pe iatric retinal tumor! occurs in $oth spora ic an familial forms" The spora ic retino$lastomas e#elop within the first % years of life an are generally unilateral" In contrast! familial retino$lastomas usually present within the first year of life an are characteri'e $y multiple tumors in#ol#ing $oth eyes" The penetrance of the RD/ mutation in these families is o#er 90 percent" The retino$lastoma gene pro uct is a nuclear protein important for cell cycle regulation" The RD/ gene pro uct .R$ protein0 $in s to! an se(uesters! cyclin D as well as 394! a transcription factor lea ing to the =/*6 cell cycle transition" R$ inhi$its the a$ility of 394 to $in DNA an initiate transcription of the genes for DNA synthesis! such as c*my$ an c*myc" A mutation in RD/ promotes unregulate cell growth through increase 394 acti#ity"

)i*4raumeni 6yn rome an p&: In /9%9! p&: was first i entifie as a cellular nuclear protein associate with the 6C;0 tumor #irus" It was not until /9?9 that p&: was recogni'e as a tumor suppressor gene an i entifie as a germline mutation associate with )i*4raumeni syn rome! a familial clustering of $reast cancer! soft tissue sarcomas! $rain tumors! osteosarcoma! leu+emia! an a renocortical carcinoma" Affecte in i#i uals e#elop cancer $y age %0 through somatic loss of the wil *type p&: allele" Inacti#ation of the p&: gene is one of the most etecta$le genetic efects in tumors" The p&: protein plays a crucial role in preser#ing the integrity of the cell-s genome $y temporarily halting the cell cycle in response to amage! allowing a e(uate time for DNA repair prior to replication" In instances of se#ere amage! the p&: protein is capa$le of triggering programme cell eath! conse(uently eliminating amage cells $efore replication can occur" Dy stimulating synthesis of nuclear proteins! such as =a ;&! p&: may in irectly facilitate DNA repair .4ig" 9*/90" =i#en its importance in pre#enting replication of a amage genome! p&: has $een christene the Fguar ian of the genomeG7 intact p&: function is crucial for tumor pre#ention" 4amilial A enomatous <olyposis an the A<C =ene The a enomatous polyposis coli .A<C0 gene mutation was first locali'e in /99/ in patients with a rare autosomal ominant form of inherite colorectal cancer +nown as familial a enomatous polyposis .4A<0" 4A< is characteri'e $y the e#elopment of multiple intestinal a enomas an nearly /00 percent progression to colorectal carcinoma within the life span of untreate in i#i uals" 4A< is a systemic isease with a phenotype that may inclu e uo enal a enomas or carcinoma! esmoi tumors! man i$ular osteomas! congenital hypertrophy of the pigmente retinal epithelium! an cutaneous epi ermoi tumors" 4A< results from a germline mutation in the A<C gene! locate on chromosome &(9/! lea ing to pro uction of a truncate A<C protein" Although the exact function of the A<C protein is un+nown! this intracellular molecule $in s to! an in uces! the egra ation of $*catenin! a glycoprotein associate with $oth cell*cell a hesion an intracellular signaling" 2utations in the A<C gene ha#e $een foun in o#er ?0 percent of spora ic colorectal cancers! suggesting that this mutation! li+e that of p&:! is important in the pathogenesis of spora ic tumors" 1ere itary 2alignant 2elanoma 6tu ies of melanoma prone families .familial malignant melanoma0 le to the locali'ation of the responsi$le gene" This gene! i entifie on 9p9/! enco es a protein +nown as p/@! $elonging to a family of proteins that inhi$it the acti#ity of cyclin* epen ent +inases .CD,s0" Cyclin* epen ent +inase inhi$itors! li+e p/@! mo ulate the mechanism that ri#es cells through mitosis an DNA replication" CD, inhi$itor genes act as tumor suppressors! an efunctionali'ing mutations in CD, inhi$itor genes are associate with tumor e#elopment" =enetic analysis of melanoma*prone Dutch +in re s re#eale intermarriage $etween two families with germline p/@ mutations" This pro#i e the uni(ue opportunity to stu y two in i#i uals homo'ygous for p/@ mutations at $irth" One of these in i#i uals sur#i#e to the age of fifty*fi#e with no e#i ence of melanoma! an is thought to ha#e ie of an intraa$ ominal a enocarcinoma" The other in i#i ual e#elope three malignant melanomas $y age fifteen" This unusual human experiment

emonstrates that the penetration an expressi#ity of the p/@ mutation is highly #aria$le" The o#erall contri$ution of p/@ mutations to melanoma inci ence is low7 stu ies of wea+ly familial an spora ic melanomas emonstrate a #ery low rate of p/@ mutation" 2ultiple 3n ocrine Neoplasia The multiple en ocrine neoplasia .23N0 syn romes are characteri'e $y autosomal ominant inheritance of altere proliferation in specific en ocrine glan s" There are three istinct 23N syn romes8 ./0 23N I! characteri'e $y pituitary! parathyroi ! an pancreatic en ocrine tumors7 .90 23N IIA! characteri'e $y pheochromocytoma! me ullary thyroi cancer! an parathyroi tumors7 an .:0 23N IID! characteri'e $y pheochromocytoma! me ullary thyroi cancer! ocular an oral neuromas! gastrointestinal ganglioneuromatosis! an marfanoi $o y ha$itus" The gene for 23N I has $een mappe to chromosome //(/:! although its specific location has not $een i entifie " <e igree an tumor tissue stu ies of 23N I suggest that this gene $elongs to the tumor suppressor gene family" 23N IIA an IID constitute genetically separate syn romes! which are go#erne $y an oncogene rather than a tumor suppressor gene" 23N II families ha#e ominant germline mutations in the ret proto*oncogene! which enco es a growth factor receptor" 4amilial Dreast an O#arian Cancer Cancer suscepti$ility genes associate with $reast an o#arian cancer inclu e DRCA* / an DRCA*9! presume tumor suppressor genes on chromosomes /%(9/ an /:(/9! respecti#ely" In families with a high rate of $reast cancer! i"e"! at least four cases per family! approximately &0 percent of affecte in i#i uals ha#e mutations in DRCA*/ an :0 percent in DRCA*9" In families with high rates of $oth $reast an o#arian cancers! %& percent are attri$uta$le to DRCA*/ an 9: percent to DRCA*9" DRCA*9 is most often associate with male $reast cancer! an inherite mutations in DRCA*9 may $e in#ol#e in /& percent of all male $reast cancer" 4amilies with germline mutations in DRCA*9 also are at increase ris+ for prostatic malignancy" In the high*ris+ families comprising the lin+age stu ies of DRCA*/! inheritance of a DRCA*/ mutation was associate with a greater than ?0 percent lifetime ris+ of $reast cancer in the female family mem$ers" 6tu ies of Ash+ena'i Bewish families $earing a particular DRCA*/ mutation! /?& elA=! emonstrate o#erall penetrance of this mutation at :? percent $y age forty! @9 percent $y age fifty! an ?& percent $y age sixty*fi#e" The functions of the DRCA*/ an DRCA*9 gene pro ucts are un+nown" 3pi emiologic stu ies suggest that mutations in the gene associate with ataxia telangiectasia .AT0 are also associate with an increase ris+ of $reast cancer" Approximately 9 percent of the population are hetero'ygous carriers of a efecti#e AT gene allele! an the proportion of $reast cancer attri$uta$le to AT gene carriers is approximately ; percent" 1ere itary Nonpolyposis Colorectal Cancer 1ere itary nonpolyposis colorectal cancer .1N<CC0 was first escri$e $y Al re Aarthin! a pathologist at the Uni#ersity of 2ichigan! in /?9&" 1is seamstress ie at an early age of cancer of the Ffemale organsG an was a mem$er of a family with a high inci ence of colon! en ometrial! an gastric cancer" In /9@@ 1enry )ynch escri$e what he calle the cancer family syn rome in a stu y of two large

2i western families with a high inci ence of colon cancer" In /99& the International Colla$orati#e =roup on 1N<CC propose the Amster am criteria as a efinition for 1N<CC .Ta$le 9*%0" The molecular $asis for 1N<CC was characteri'e $y lin+age stu ies of +nown colon cancer suscepti$ility genes! such as p&: an A<C! in families that met the Amster am criteria" Although no lin+age to these genes was foun ! researchers isco#ere a high rate of mutation in DNA microsatellites! which are short repetiti#e se(uences of mono*! i*! or tri* nucleoti es intersperse throughout the normal genome" They postulate that the 1N<CC*associate mutations pro ucing this Fmicrosatellite insta$ilityG enco e factors re(uire for DNA replication an repair" A /99: stu y use microsatellite mar+ers to map 1N<CC to 9p/&*/@! an a su$se(uent stu y lin+e 1N<CC to mutations on :p" It is thought that o#er %0 percent of cases of 1N<CC in#ol#e mutations in one of four i entifie mismatch repair genes" These genes enco e proteins that recogni'e! excise! an repair mismatche nucleoti es! preser#ing the integrity of the genome" A efect in mismatch repair theoretically sets the stage for accumulation of the multiple uncorrecte mutations re(uire for cancer e#elopment" An inherite ten ency to e#elop cancer is thought to $e associate with / to & percent of all colorectal cancers! & to /0 percent of $reast cancers! an & to /0 percent of o#arian cancers" 2any of the inherite cancer pre isposition syn romes in#ol#e germline mutations in genes that also contri$ute to the e#elopment of spora ic cancers! such as p&:! A<C! an 2)1*/" 4amilies with inherite cancer pre isposition syn romes pro#i e the most stri+ing examples of tumor suppressor genes in action! $ut most tumors associate with tumor suppressor gene ysfunction are spora ic" These syn romes! howe#er! present the opportunity to stu y carcinogenesis in mo els that are rele#ant to more common! nonfamilial malignancies" 4unctional Alterations in Carcinogenesis Tumor progression in#ol#es ac(uisition of se#eral a$ilities $y the malignant colony" These cells must $e a$le to ./0 in#a e the $asement mem$rane an surroun ing tissues through the pro uction of proteases! .90 recruit $loo #essels to support the growth of the tumor mass! .:0 a#oi estruction $y effector cells of immune sur#eillance! such as N, cells! .;0 mo#e through tissues! a process that re(uires pro uction an recruitment of cell a hesion molecules an chemotactic cyto+ines! an .&0 tra#el to istant sites! a here! an esta$lish a new tumor colony" There are many parallels $etween fetal e#elopment an malignant transformation" During e#elopment! the $eha#ior of in i#i ual cells is etermine $y regulate e#elopmental programs that result in the formation of cohesi#e cell colonies" The process of tumorigenesis in#ol#es the isruption of these normal e#elopmental programs" This principle is clearly illustrate in the e#elopment of a teratoma! where the resulting tumor attempts to recapitulate an intact organism" Normal em$ryonic e#elopment an tissue homeostasis epen on specifically time intracellular communication" 2uch of this communication results from the pro uction an release of growth factors! such as epi ermal growth factor .3=40! as well as signals eli#ere $y a hesion molecules through cell*cell contact" Tumorigenesis is characteri'e $y the $rea+ own of these growth regulatory interactions! a process that in#ol#es $oth the acti#ation an expression of proto*oncogenes! an the inacti#ation

of suppressor genes" Although tumors ha#e long $een thought of as autonomous tissues! it is clear that a tumor coul not exist without its surroun ing stroma" Certain tumors re(uire particular en#ironments in which to grow! as e#i ence $y the characteristic metastatic locations of many soli tissue tumors" An o$#ious example of a tumor*host epen ency is angiogenesis! $ut there are many other possi$ilities for tumor growth regulation $y the microen#ironment of a tumor" The result of carcinogenesis is the isruption of the normal homeostatic relationship $etween the transforme cell an its surroun ing normal tissues" Relationships Detween Tumors an Normal 1ost Tissues )ocal In#asion During the transition from in situ to in#asi#e carcinoma! tumor cells must cross the $asement mem$rane an enter the surroun ing stromal tissue" The intact $asement mem$rane! a ense matrix of collagen! glycoproteins! an proteoglycans! oes not contain pores large enough for intact cells to penetrate! an hence tumor in#asion must in#ol#e partial estruction of this $arrier" On the other si e of the $asement mem$rane is the tissue stroma! a collection of fi$ro$lasts! myofi$ro$lasts! an other stromal cells" These cells acti#ely participate in tumor in#asion" The process of local tumor in#asion can $e i#i e into three steps8 tumor cell a hesion! matrix issolution! an migration" Tumor Cell A hesion The growth of normal tissues is characteri'e $y cell*cell a hesion! a process lin+e to cellular proliferation an ifferentiation! such that a cell losing this contact un ergoes in#olution" During carcinogenesis! the re(uirement for cell*cell a hesion is lost! an the single cell infiltrates local tissues in a relati#ely in epen ent manner" Cell*cell a hesion an the growth regulation pro#i e $y this contact are me iate $y cell a hesion molecules .CA2s0! which are complex transmem$rane glycoproteins present on the surface of $oth epithelial an stromal cells" These a hesion molecules also interact with the surface of the $asement mem$rane! which contains receptor glycoproteins such as laminin! type IC collagen! an fi$ronectin" CA2s are i#i e into four main classes accor ing to their structure an general function" These inclu e the ca herins! the integrins! the selectins! an the immunoglo$ulin superfamily receptors" In a ition! other cell surface molecules! such as the ma5or histocompati$ility .21C0 molecules an CD;;! contri$ute to tumor cell a hesion .4ig" 9*/:0" Ca herins Ca herins are transmem$rane glycoproteins that me iate calcium* epen ent homophilic cell*cell a hesion" There are three ma5or classes of ca herins8 3* ca herins! me iating a hesion $etween epithelial cells! N* ca herins! controlling a hesion in ner#e! car iac! an pulmonary tissues! an <*ca herin! pro#i ing a hesion in intestinal! car iac! an pulmonary tissues" The intracellular portion of the ca herin is associate with the actin cytos+eleton as well as with molecules in#ol#e in transmitting growth regulatory signals to the nucleus" Analysis of human epithelial tumors re#eals a consistent loss of 3*ca herin expression! an cell line transfection stu ies suggest that reintro uction of 3*ca herin into tumor cells inhi$its their in#asi#e a$ility" Integrins

Integrins are hetero imeric transmem$rane glycoproteins that me iate a hesion $etween epithelial cells an extracellular matrix proteins" 2ore than 90 ifferent types of integrins ha#e $een i entifie ! many of them with tissue specificity" Integrins commonly recogni'e extracellular matrix proteins $y a tripepti e se(uence of Arg* =ly*Asp present in fi$ronectin! #i$ronectin! an a #ariety of other a hesion proteins" The surface expression of integrins an their interaction with extracellular proteins can $e mo ulate $y cyto+ine factors such as tumor*necrosis factor .TN40! interferon* gamma .I4N*g! or transforming growth factor* $/ .T=4*$/0" The $in ing of integrins to their ligan s results in transmission of signals for cellular proliferation an ifferentiation" The process of tumor in#asion or metastasis may in#ol#e loss of appropriate integrin*me iate a hesion an signaling! resulting in cellular acti#ation an esta$lishment of tissue*specific metastatic colonies" 6electins 6electins are a hesion molecules present on en othelial cells an hematopoietic cells" These cell surface molecules go#ern the processes of leu+ocyte a hesion an homing" Three types of selectins ha#e $een escri$e 8 ./0 3*selectin! or en othelial*leu+ocyte a hesion molecule*/! .90 <*selectin! or granule mem$rane protein /;0! an .:0 )* selectin! or leu+ocyte*specific selectin" 3*selectin an <*selectin are expresse on acti#ate en othelial cells an me iate the $in ing of leu+ocytes to en othelial cells" )*selectin! foun on the surface of leu+ocytes! controls the homing of leu+ocytes to lymphoi organs" 3*selectin has emonstrate an a$ility to recogni'e )ex .6)L0 antigen! a complex car$ohy rate that is expresse at high le#els in metastatic colorectal cancers" Altere expression of cell surface car$ohy rates may $e one of the mechanisms of tumor progression" Immunoglo$ulin 6uperfamily The Ig superfamily is characteri'e $y an immunoglo$ulin*li+e extracellular omain! an fi$ronectin type III repeats" These molecules me iate homotypic an heterotypic cell*cell interactions" Neural cell a hesion molecule .N*CA20 is one example of the Ig superfamily" The protein pro uct of the DCC gene! locate on chromosome /?(! shows significant homology to N*CA2" This gene is mutate in metastatic colorectal cancers! suggesting that normally functioning DCC protein is important in pre#enting cell in#asion an Nor metastasis" 6e#eral other cell surface molecules contri$ute to the cell*cell interactions go#erning normal tissue $eha#ior" These inclu e ma5or histocompati$ility .21C0 molecules! particularly 21C class I" 21C class I molecules complex with en ogenously processe pepti es! such as #iral proteins! an target a$normal or infecte cells for estruction $y immune effector cells" One of the ways that a$normal tumor cells hi e from immune sur#eillance is $y altere expression of 21C molecules" Another cell surface molecule with a special role in tumorigenesis is CD;;! a protein present in #arious isoforms create $y alternati#e mRNA splicing" The CD;; splice #ariants are thought to facilitate lymphocyte recirculation an homing to lymphoi tissues" In a ition! CD;; is present on the surface of epithelial cells! an particular isoforms are o#erexpresse on $oth primary an metastatic tumors" 2atrix Dissolution After a hesion of tumor cells in experimental mo els of tumor infiltration! a locali'e 'one of lysis is pro uce in the $asement mem$rane near the point of tumor cell

contact" This matrix lysis occurs from 9 to ? hours after tumor cell attachment as a result of en'ymes secrete irectly $y the tumor cell an $y stromal fi$ro$lasts" These en'ymes $elong to a family +nown as the metalloproteinases .22<s0" 3xamples of these en'ymes inclu e interstitial collagenases! type IC collagenases! an stromelysins" Natural protease inhi$itors! +nown as tissue inhi$itors of metalloproteinases .TI2<s0! pro uce either $y the host or $y the tumor itself! can counteract this process" Once the $asement mem$rane $arrier is lyse ! tumor cells are free to migrate into the surroun ing stromal tissue .4ig" 9*/;0" 2igration In a ition to a hesion an proteolysis! acti#e tumor motility is re(uire for the in#asion an metastasis of tumors" In a ramatic in #i#o stu y $y Aoo in /9&?! microcinematography was use to o$ser#e irectly the migration of ra$$it carcinoma cells from the #asculature of the ra$$it-s ear" )i+e most cellular functions! tumor cell motility in#ol#es $oth fixe cell surface interactions an solu$le factors" 2orphologic stu ies show that! li+e leu+ocytes! tumor mo#ement is characteri'e $y ame$a*li+e pseu opo extension" This mo#ement re(uires coor ination of multiple steps! inclu ing cellular protrusion an new a hesion formation at the lea ing e ge an release of ol a hesi#e interactions at the trailing e ge" A #ariety of cyto+ines stimulate motile responses in tumor cells" These inclu e tumor cell* eri#e cyto+ines! such as autocrine motility factor! autotaxin! an scatter factor .Ta$le 9*?0" 2any a hesion molecules! particularly those foun in the extracellular matrix! such as laminin! collagen! fi$ronectin! an throm$ospon in! ser#e as tumor cell attractants in motility assays" Angiogenesis Angiogenesis! or the formation of new $loo #essels! is important for all phases of tumor progression .4ig" 9*/&0" Aithout new #essel growth! tumors woul (uic+ly outstrip their local nutrient supply an woul $e una$le to form new colonies after istant metastasis" )i+e all aspects of tumor growth! the process of angiogenesis in#ol#es complex signals eli#ere $etween the tumor cell an the host en#ironment" At the initiation of angiogenesis! en othelial cells in #essels near the tumor site are stimulate to egra e the extracellular matrix" This is followe $y migration of en othelial cells into the peri#ascular stroma in the irection of the angiogenic stimulus! initiating a capillary sprout that e#entually forms a tu$ular #essel" =rowth of a tumor colony $eyon / cm: in si'e re(uires #asculari'ation of the tumor through angiogenesis" Angiogenesis is partially me iate $y solu$le locally secrete factors" These factors inclu e8 $asic fi$ro$last growth factor .$4=40! aci ic 4=4 .a4=40! #ascular en othelial growth factor .C3=40! platelet* eri#e en othelial cell growth factor .<D* 3C=40! transforming growth factors a an $ .T=4*a an *$0! angiogenin! TN4*a! an interleu+in*? .I)*?0 .Ta$le 9*90" Tumor angiogenesis is a complex process! only partially explaine $y the presence of angiogenic factors secrete $y tumor cells" Tumor cells themsel#es o release angiogenic factors such as C3=4 an 4=4 as well as se#eral that ha#e not yet $een completely purifie or characteri'e " Tumor angiogenesis may occur through own* regulation of normally secrete angiogenesis inhi$itory su$stances! such as throm$ospon in" Tumors may $e a$le to recruit macrophages an then acti#ate them to secrete angiogenic factors such as TN4 an I)*?"

The e#elopment of angiogenic potential in a tumor may $e an important in icator of its $iologic $eha#ior" 4or example! the presence of increase #ascularity in early .6tage I or II0 $reast cancer specimens in icates a significantly higher chance of tumor recurrence" Angiogenesis in early stage $reast cancer is also correlate with the presence of lymph no e metastasis uring initial operati#e staging! in icating that angiogenesis is closely lin+e with metastatic potential" It has also $een suggeste that e#elopment of metastatic potential is ac(uire at a critical ensity of $loo #essels in a primary $reast cancer lesion" These o$ser#ations raise the possi$ility that antiangiogenesis agents! such as analogues of the fungus* eri#e angiogenesis inhi$itor fumagillin! might pro#e $eneficial in the treatment of malignancy" 2etastasis 2etastatic tumors e#elop as clones arising from a heterogeneous primary tumor" It is assume that when a cell within a tumor reaches a particular stage of #irulence! it ac(uires the a$ility to metastasi'e" Recent e#i ence suggests that tumor cell metastasis re(uires multiple host*tumor interactions! an the process of metastasis pro$a$ly $egins early in the growth of the primary tumor" The metastatic cell must $e a$le to o more than simply grow an i#i e in a new location7 it must also $rea+ away from the original tumor population! in#a e through the $asement mem$rane into a $loo #essel! tra#el an a here to a istant site! an in uce angiogenesis" These acti#ities re(uire coor inating the processes of proteolysis! motility! a hesion! growth factor responsi#eness! an angiogenic acti#ity" 6ince all of these processes are naturally occurring functions of growth an e#elopment! the $asic efect of metastasis must lie in the a$errant regulation of these processes" A hesion is an o$#ious component of metastatic $eha#ior! $oth in the initial loss of attachment to the primary tumor cell mass an in the preference of certain tumors for metastatic sites" Despite a #ances in our un erstan ing of the mechanisms of cellular a hesion! it is still ifficult to efine the a hesion re(uirements for metastasis" 2any of the a hesion e#ents pre#iously escri$e are implicate in the e#elopment of metastatic lesions" An example of this is the interaction of fi$ronectin! collagen! an laminin in the extracellular matrix with tumor cell receptors of the integrin an nonintegrin #arieties" 6ome organ*specific a hesion e#ents ha#e $een i entifie ! supporting the hypothesis that specific a hesion is the reason for the preferential metastatic sites of certain tumors" Doth in #itro an in #i#o stu ies show that interfering with a hesion molecules can inhi$it metastasis" The e#elopment of metastatic potential in a tumor cell clone is correlate with the presence of proteolysis! a process alrea y escri$e for its role in tumor cell in#asion an migration through tissue" Dloc+a e of certain proteases! such as uro+inase*type plasminogen acti#ator! pre#ents esta$lishment of metastasis" Compare with nonmetastatic cells! metastatic human melanoma cells express higher le#els of tissue factor! the ma5or cellular initiator of the plasma coagulation protease casca es" Tissue factor may promote metastasis $y allowing increase tumor*en othelial cell a hesion as well as facilitating transmigration of tumor cells across the en othelium" 2etastasi'ing tumors ha#e a pre ilection for selecte organ sites .Ta$le 9* /00" In human $eings! colon tumors fre(uently metastasi'e to the li#er! renal cell carcinoma to the lung! melanoma to the lung an $rain! prostate cancer to the $one! $reast cancer to the lung! li#er! $rain! an $one! an ocular melanoma to the li#er" 6election of a

metastatic site $y a particular tumor is pro$a$ly go#erne $y the a hesion an growth factor characteristics of the metastatic site an the re(uirements of the metastatic tumor" 4or example! metastatic melanoma cells express more of the integrin C)A*; than o nonmetastatic cells! suggesting that this a hesion molecule an its ligan ! C* CA2! may ha#e some role in etermining the specific en othelium for locating the metastatic eposit .4ig" 9*/@0" The role of the regional lymphatics in neoplasia in general an in metastasis in particular is as contro#ersial as it is important" 3arly theories of cancer progression postulate that regional lymph no es pro#i e a filter that was an effecti#e! $ut temporary! $arrier to the sprea of tumor cells" It is now thought that the properties of the tumor cells themsel#es! rather than the filtration capacity of the lymph no es! etermine whether neoplastic cells are trappe within no es or allowe to isseminate" The regional no es may also $e in#ol#e in the initiation of systemic immunity to tumors" 4or example! a opti#e transfer of lymphoi cell populations eri#e from regional lymph no es has $een shown to in uce tumor allograft immunity in normal animals" Among the many tumor metastasis mo els! howe#er! there are su$stantial ifferences in the (uality an (uantity of immune responses to tumors! an the functional contri$ution of regional no es to systemic tumor immunity is unclear" Tumor cell entrapment in the capillary $e of istant organs is a necessary prelu e to secon ary tumor growth" Although the morphologic aspects of tumor cell entrapment are stu ie extensi#ely! little is +nown a$out the ynamics of the process" 3xposure of the capillary $asement mem$rane is a result of the normal an continuous physiologic process of en othelial cell* shre ing an may allow a hesion of tumor em$oli" <latelet a herence to amage regions of the $asement mem$rane! followe $y egranulation! causes further retraction of en othelial cells an augments attachment of tumor em$oli or platelet*tumor cell em$oli" 4i$rin eposits aroun a tumor em$olus are fre(uently o$ser#e ! $ut the role of fi$rin in tumor cell entrapment an metastasis is uncertain" Theoretically! a protecti#e coat of fi$rin surroun ing the tumor em$olus shiel s the neoplastic cells from the host immune response an $loo tur$ulence" Increase coagulation is commonly o$ser#e in patients with cancer an may $e relate to the increase in throm$oplastin foun in tumors" 6ome neoplasms pro uce large (uantities of procoagulant*A! which irectly acti#ates factor L of the clotting casca e" A re uce rate of $loo flow in the #icinity of the tumor lea s to increase trapping of circulating tumor cells an contri$utes to the sur#i#al of alrea y trappe cells" The use of anticoagulants in the control of metastasis is $ase on these o$ser#ations" 6tu ies using oncogene transfection pro#i e a mo el for acti#ation of the cellular responses that are re(uire for tumor metastasis" 2any oncogenes! when transfecte into appropriate recipient cells! such as fi$ro$lasts an epithelial cells! are capa$le of in ucing metastatic a$ility" 6ome of these FmetastaticG oncogenes inclu e mutate ras! #*src! #*fes! #* fms! an p&:" )ac+ of expression of the Fmetastasis suppressorG gene! nm9:! may also $e responsi$le for the e#elopment of metastatic isease" This gene was first i entifie for its ecrease expression in murine melanoma tumor lines" Decrease expression of nm9: is also associate with metastasis in $reast! colon! renal cell! hepatocellular! lung! an s(uamous cell carcinomas" Although there is no efinite proof that lac+ of nm9: expression results in metastasis! this conclusion is

supporte $y research showing that transfection of nm9: into melanoma cell lines results in ecrease tumor inci ence! metastatic potential! an cyto+ine responsi#eness" The exact mechanism of metastasis suppression $y nm9: is un+nown! $ut e#i ence suggests that this gene is important for signal trans uction uring e#elopment" 2etastasis is a multistage process in which tumor cells ac(uire more an more autonomy regar ing growth factor an a hesion re(uirements" A complex process with no uni#ersally applica$le mechanism! metastasis is epen ent on the characteristics of the tumor .the Fsee G0! an the microen#ironment of its implantation site .the FsoilG0" Autocrine 2echanisms <ro uction of Tumor =rowth 4actors The autocrine mo el of tumorigenesis hol s that tumor formation! li+e the process of em$ryogenesis! occurs through a coor inate series of cellular signaling e#ents! regulate $y growth factors" Transformation of normal cells to malignant $eha#ior may result from either increase pro uction of stimulatory growth factors or ecrease pro uction of inhi$itory growth factors" In /?9@ 6ir =eorge Deatson in =lasgow emonstrate that oophorectomy coul pro uce tumor regression in patients with $reast carcinoma! suggesting that secrete steroi hormones support tumor growth" The molecular characteri'ation of tumor growth factors $egan with the o$ser#ation that polypepti es secrete $y a #ariety of retro#irally! chemically! or oncogene*transforme cell lines coul in uce tumor growth or cellular transformation" The first correlation $etween an oncogene an a normal cellular protein was emonstrate when the amino aci se(uence of the sis oncogene pro uct isplaye significant homology to the $ chain of platelet* eri#e growth factor .<D=40" One example of the interplay $etween stimulatory an inhi$itory growth factors is that of the transforming growth factors T=4*a an T=4*$" T=4* a an T=4*$ were originally name for their a$ility to re#ersi$ly in uce anchorage*in epen ent growth in fi$ro$lasts" T=4*a$elongs to a family of growth*stimulatory cyto+ines! all of which share a common receptor with epi ermal growth factor .3=40" As expecte ! these cyto+ines ha#e similar acti#ities! which inclu e regulation of the growth an ifferentiation of normal an neoplastic epithelial cells" T=4*$! on the other han ! is an inhi$itor for cells respon ing to growth factors of the T=4*afamily" This protein normally pro#i es autocrine growth inhi$ition of epithelial cells an also inhi$its the in #itro growth of some tumor cell lines" Recent ata suggest that the e#elopment of malignancy can $e correlate with increase autocrine growth stimulation $y T=4*a! or ecrease autocrine growth inhi$ition $y T=4*$" Other growth factors reporte to $e in#ol#e in tumorigenesis inclu e insulin*li+e growth factor*/ .I=4*/0! platelet* eri#e growth factor .<D=40! fi$ro$last growth factor .4=40! hepatocyte growth factor .1=40! fi$ronectin! transferrin! amphiregulin .a mem$er of the 3=4 family0! an interleu+in*@ .I)*@0 .Ta$le 9*//0" I)*@ may $e an inhi$itor of tumor growth in early tumor stages! switching to a stimulatory factor for metastatic lesions" In one stu y! melanoma cells o$taine from primary tumors exhi$ite growth inhi$ition upon in #itro culture with I)*@" =rowth of metastatic melanoma cells! howe#er! was stimulate significantly $y culture in I)*@" Ac(uisition

of the a$ility to proliferate in response to cyto+ines such as I)*@ may $e one of the cellular e#ents lea ing to metastatic isease" Constituti#e Acti#ation of =rowth 4actor Receptors In some tumors! loss of normal growth regulation occurs as a result of altere expression of growth factor receptors .4ig" 9*/%0" 3ither constituti#e acti#ation of a growth factor receptor or an increase in growth factor receptor num$er woul ha#e the same effect as an increase in le#els of the correspon ing growth factor! e"g"! an increase in receptors for epi ermal growth factor .3=4R0 may contri$ute to tumor growth in s+in! colon! an $reast cancers" The er$D oncogene pro uct is a transmem$rane receptor similar to the 3=4 receptor except that it is constituti#ely acti#ate ! i"e"! a$le to generate a mitogenic signal in the a$sence of 3=4 $in ing .4ig" 9*/?0" 3xpression of this oncogene is associate with poor prognosis in $reast cancer" 6e#eral other receptors enco e $y oncogenes! such as +it! ros! met! ret! an tr+! emonstrate eletions of ligan *$in ing omains" The 23N IIA an IID syn romes are associate with ominant acti#ating germline mutations of ifferent regions of the ret proto*oncogene" 2urine em$ryo stu ies emonstrate that this gene enco es a growth factor receptor foun on su$sets of cells in the central an peripheral ner#ous system" In a ition! ret is consistently expresse in $oth familial an nonfamilial neuro$lastomas! pheochromocytomas! an me ullary thyroi carcinomas as well as in normal thyroi an a renal glan s" An interesting emonstration of the cumulati#e effect of mutations on tumorigenesis is pro#i e $y the relationship $etween mismatch repair efects an T=4*$ acti#ity" As escri$e pre#iously! a characteristic of eficient mismatch repair is alteration of microsatellite DNA" The gene enco ing the epithelial cell receptor for T=4*$! the T=4*$ receptor type 9 .T=4*$ RII0! contains a microsatellite site consisting of a string of ten a enosine repeats" In in i#i uals with 1N<CC an mismatch repair efects this gene is commonly mutate an the resulting T=4*$ RII is ysfunctional" This results in loss of T=4*$ suppression of epithelial cell growth! an contri$utes to tumor formation" Intracellular 6ignal Trans uction Din ing of a ligan to a cell surface receptor results in an intricate casca e of intracellular reactions! ultimately in ucing transcription of appropriate cellular genes" This complex process is +nown as intracellular signal trans uction" Any alteration in the networ+ of signals responsi$le for or ere cell growth can contri$ute to carcinogenesis! an most oncogenes or tumor suppressor genes enco e proteins essential for intracellular signal trans uction" Oncogenes can $e roughly i#i e into groups accor ing to their cellular function" The small su$set of oncogenes comprising growth factors or growth factor receptors has alrea y $een iscusse " The other oncogene categories inclu e signal trans ucers such as cytoplasmic protein +inases an =T<*$in ing proteins! transcriptional regulators! an regulators of programme cell eath .apoptosis0" 6ignaling Through =rowth 4actor Receptors 3ngagement of a receptor $y an appropriate ligan in uces the assem$ly of the primary secon messenger proteins at the inner surface of the plasma mem$rane near molecules such as ras that are in#ol#e in su$se(uent $ranching pathways of signal trans uction .4ig" 9*/90" =rowth factor receptors! also +nown as receptor tyrosine

+inases! consist of three omains8 ./0 a large amino*terminal extracellular ligan $in ing omain7 .90 a short transmem$rane helix7 an .:0 an intracytoplasmic car$oxyl terminus that is a ligan *acti#ate tyrosine +inase" Din ing of a ligan growth factor to the extracellular omain results in receptor imeri'ation an phosphorylation of the intracellular portion of the receptor" This triggers recruitment of intracellular su$strates characteri'e $y src homology 9 .6190 omains to the receptor phosphotyrosine resi ues" An example of such a su$strate is the protein =r$9! which! when associate with the appropriate phosphotyrosine of an acti#ate growth factor receptor! recruits the 6os protein! a nucleoti e exchange factor" 6os then engages the ras protein an assists in its acti#ation $y exchanging guanosine iphosphate .=D<0 for =T<" This acti#ation is assiste $y yet another factor! a =T<ase*acti#ating protein .=A<0" Once ras has $een acti#ate ! it triggers a casca e of serine*threonine +inases! such as mem$ers of the raf gene family! an a group of cytoplasmic en'ymes +nown as mitogen*acti#ate +inases .2A< +inases0" These +inases me iate the reactions that $ri ge the gap $etween the cell mem$rane an the nucleus" Acti#ation of the 2A< +inases results in phosphorylation of nuclear transcription factors! such as the c*fos an c* 5un pro ucts! which are components of a transcriptional acti#ator name A<*/" c*fos an c*5un in uce transcription of the proto*oncogene c*myc! a irect regulator of the cell cycle! an stimulate the cell to progress from =/ into 6 phase! thus committing the cell to a roun of DNA replication" The signaling pathway of growth factor receptors is one of se#eral ifferent mechanisms lea ing to cellular acti#ation" Receptors that lac+ intrinsic +inase acti#ity transmit their signal through association with intracellular protein +inases! such as the pro uct of a gene calle lc+" ras $elongs to a family of proteins +nown as = proteins that transmit signals from cell surface ligan s to effectors! such as a enylate cyclase or phospholipase A9! through con#ersion of =T< to =D<" Regulation of the acti#ation states of ras an relate proteins is a crucial point in signal trans uction" To participate in signaling! ras protein must attach to the inner surface of the plasma mem$rane $y lin+ing to an isoprenyl group! a process +nown as farnesylation" 6trategies to inhi$it the ras farnesylation reaction! such as through inhi$ition of the en'yme farnesyl protein transferase .4<Tase0! are un er in#estigation as new chemotherapy agents" A ras*in epen ent signaling pathway has $een propose where$y receptor engagement acti#ates a phospholipase that hy roly'es inositol phospholipi s in the plasma mem$rane an acti#ates two a itional secon messengers8 ./0 inositol triphosphate! which triggers a signaling casca e through intracellular calcium flux! an .90 iacylglycerol! a mem$rane* associate lipi that acti#ates another protein +inase calle protein +inase C .<,C0" Acti#ate <,C is then a$le to acti#ate raf! pro ucing 2A< +inase acti#ation an lea ing to transcription of c*fos an c*5un" A recurring theme in stu ies of signal trans uction is the in#ol#ement of protein +inases" Intracellular secon messenger proteins must $e phosphorylate $y a tyrosine +inase in or er to amplify an istri$ute signals for cellular growth an ifferentiation" Although the roles of these +inases in signal trans uction are not well un erstoo ! stu ies of cellular acti#ation associate $oth receptor an nonreceptor +inase acti#ity to multiple cellular processes! such as proliferation! meta$olism! an

cytos+eletal function" 2any more pieces of the pu''le are nee e to fully un erstan the complex regulatory mechanisms go#erning signal trans uction" Cell Cycle Control Cells ta+e their cues for proliferation an ifferentiation not only from external sources such as growth factor receptors $ut also accor ing to an internal program" The cell cycle encompasses the progression from =/ phase through mitosis an is coor inate $y nuclear proteins calle cyclins" The passage of a cell through the cell cycle is tightly regulate $y a networ+ of controls that act on the transcription of cyclin genes! the egra ation of cyclin proteins! an the mo ification of cyclin* epen ent +inases $y phosphorylation" It is now recogni'e that the cell cycle is a ynamic process that inclu es perio s of arrest of cell proliferation when DNA amage occurs! presuma$ly to allow time for DNA repair to occur" <ro#isions are ma e within the cell cycle program for apoptosis in circumstances in which the cell-s genome has un ergone irrepara$le amage" Coor ination of the cell cycle is achie#e through a networ+ of cyclin* epen ent +inases .CD,s0! which un ergo programme changes in acti#ation state .4ig" 9*900" Ahen in an acti#ate state! each CD, is a com$ination of a cyclin an a +inase as well as a #ariety of other associate proteins" After acti#ation of mammalian cells! a succession of +inases! +nown as CD,;! CD,9! an CDC9! are expresse in con5unction with a series of cyclins .cyclins D! 3! A! an D0 as the cell progresses from =/ to mitosis" 3ach of the cyclin genes is transiently transcri$e uring a particular phase of the cell cycle! its mRNA translate ! an then the protein is rapi ly egra e such that its resi ence time uring the cell cycle is $rief" The elements of control o#er the cell cycle inclu e re un ant systems for regulating each step of this process" In a ition to mechanisms allowing passage of cells through the cell cycle in response to mitogenic stimuli! negati#e controls on cell cycle progression! +nown as cell cycle chec+points! are important for cell ifferentiation an senescence .4ig" 9* 9/0" Defects in these negati#e controls are associate with carcinogenesis" At least two chec+points etect DNA amage8 one at the =/*6 transition! an one at the =9*2 transition .Ta$le 9*/90" Alterations at the Cell Cycle Chec+points At the transition from =/ to 6 phase! the main target of the acti#ate +inase is the R$ protein .4ig" 9*990" The R$ protein is $oun to the transcription factor 394 uring =/" Upon phosphorylation! R$ releases 394! which in turn acti#ates the transcription of genes re(uire for 6 phase" )oss of function of the R$ protein lea s to unregulate entry of a cell into 6 phase" Upstream of R$*394! se#eral proteins control the =/*6 transition" One of these is the p&: gene pro uct" Damage to the cellular DNA in uces pro uction of p&: protein! which in turn acti#ates p9/! a protein that inhi$its all of the cyclin*CD, complexes .Ta$le 9*/:0" This results in a elay in the transition from =/ to 6 that allows time for DNA replication to occur" A cell with eficient p&: will enter 6 phase without sufficient DNA repair an replicate uncorrecte mutations" An a itional cell cycle chec+ is pro#i e $y p9%! a protein in uce $y $in ing of T=4*$ to the cell" p9% is also an inhi$itor of cyclin*CD, complexes" 4inally! p/@ is a cyclin* epen ent +inase inhi$itor an regulator of =/*6 transition whose acti#ation stimulus is not yet +nown7

germline mutations in the gene enco ing p/@ are associate with familial malignant melanoma" The =9*2 cell cycle transition is also incompletely un erstoo ! $ut it appears to in#ol#e the pro uct of the ataxia telangiectasia .AT0 gene" In i#i uals with AT exhi$it a high fre(uency of chromosomal $rea+s after irra iation! an their cells o not un ergo proper arrest in =9after ra iation" In i#i uals carrying a germline mutation in the AT gene are at an increase ris+ for cancers! presuma$ly through loss of the tumor suppressor function of the AT gene pro uct" 3#i ence for another type of cell cycle regulator comes from examination of speciali'e nucleoprotein structures +nown as telomeres" Telomeres are locate at the en s of chromosomes an are essential for maintenance of chromosomal sta$ility" In immortali'e cell cultures! telomere length is maintaine $y the en'yme telomerase" Telomerase is a$sent! howe#er! in almost all normal human cells" Aith repeate replication of the chromosome! the telomere en s are lost! causing telomeres to un ergo progressi#e shortening in normal human cells" This process lea s to a limite life span for normal cells! as cells lac+ing telomeric se(uences! una$le to replicate! $ecome senescent" Telomeres are thought to represent an internal cloc+ $y which the life span of somatic cells is measure " 6tu ies of human tumors show no loss of telomere si'e with repeate replication an an increase in telomerase acti#ity! suggesting that escape from the regulation cause $y telomeric shortening may $e important in tumorigenesis" Regulation of Apoptosis In or er for tissues to maintain a normal state! cells su$5ect to renewal must in#olute so that the proliferation an in#olution rates are $alance " This Fprogramme cell eathG is +nown as apoptosis an ! in contrast to cell necrosis! is characteri'e $y cytoplasmic shrin+ing! nuclear chromatin con ensation! an DNA fragmentation" Defects resulting in loss of normal apoptosis are associate with tumor formation" 4or example! the $cl*9 oncogene was i entifie in follicular lymphomas an foun to promote cell sur#i#al rather than proliferation" A family of genes whose pro ucts interact with one another to regulate cell eath $y apoptosis inclu es $cl*9 .4ig" 9* 9:0" DAL! a protein i entifie $y its association with the $cl*9 gene pro uct! counteracts the sur#i#al*promoting effects of $cl*9" Although many ifferent stimuli are a$le to in uce apoptosis! most result in in#ol#ement of the DALN$cl*9 interchange7 for instance! p&: may ser#e as a cellular sur#eillance factor $y in ucing either growth arrest or cell eath! epen ing upon the cellular circumstances" Transcription of DAL protein is in uci$le $y p&:" Therefore! p&: causes growth arrest through acti#ation of the p9/ gene! or apoptosis through in uction of DAL" Other regulators of apoptosis inclu e TN4*R/! a cell surface receptor that promotes apoptosis when acti#ate $y its ligan ! TN4*$! an the interleu+in*/$* con#erting en'yme .IC30 family! a group of cysteine proteases capa$le of in ucing apoptosis" 4inally! #arious growth factors an cyto+ines such as I=4*/ may act on the apoptotic pathway to promote cell sur#i#al" 6UR=ICA) 2ANA=323NT O4 <RI2AR> TU2OR6 =eneral Consi erations The surgeon-s role in the treatment of tumors #aries with the type of cancer $ut inclu es iagnosis! clinical staging .Ta$le 9*/;0! operati#e resection for cure an local

isease control! pathologic staging or palliation! an the management of me ical con itions common to the cancer patient .Ta$le 9*/&0" The ma5or goal of treatment is to pro#i e the $est chance for cure with the $est functional an cosmetic result" <rimary curati#e operations may $e performe on patients with $reast! lung! uterine! an large*$owel cancer" In other forms of cancer! such as lymphoma! the surgeon-s role may $e iagnostic! with a possi$le contri$ution to staging7 in patients with leu+emia! the only surgical role may $e pro#ision of #ascular access for long*term a ministration of chemotherapy or the management of associate complications" ,nowle ge of clinical an pathologic staging is important7 accurate iagnosis an assessment of the extent of tumors are essential to appropriate treatment" <athologic staging gi#es insight into the natural course of the neoplasm! which is necessary to etermine further treatment plans an to e#aluate their efficacy .Ta$les 9*/@ an 9* /%0" The surgeon uses physical examination! roentgenography! ultrasonography! compute tomography .CT0! an magnetic resonance imaging .2RI0 techni(ues to etermine if the neoplasm is potentially cura$le $y surgical remo#al .Ta$le 9*/?0" 6tu ies to preclu e metastases are in icate when they are cost*effecti#e an woul su$stantially alter surgical treatment" The asymptomatic patient with a / cm $reast mass an clinically negati#e regional lymph no es shoul not re(uire li#er or $one ra ionucli e scan or a$ ominothoracic CT scans! as these tests woul not $e cost* effecti#e" 1owe#er! the use of CT scans of the chest in a patient with lung cancer can effecti#ely help to stage the isease an to ascertain whether surgery with operati#e resection is appropriate" 6urgical resecta$ility is also etermine $y the tumor-s relation to! an egree of in#asion into an aroun ! #ital structures" In#asi#e an nonin#asi#e ra iologic stu ies are extremely helpful in outlining the goals of operati#e management an efining the operati#e approach in specific patients e"g"! portal #ein com$ine with hepaticNsplenic artery occlusion enotes nonresecta$ility in patients with carcinoma of the pancreas! although surgical $ypass may $e necessary for $iliary or gastric outlet o$struction" The surgeon has a ma5or role in isease pre#ention an patientNfamily counseling" The extent of an operation may $e relate to the presence of a itional precancerous lesions or to a strong family history of site*specific cancers" 4or example! a patient with cancer of the colon an numerous colonic a enomas may $e treate $y a total a$ ominal colectomy rather than simple excision of the cancer*affecte segment of large $owel" In some circumstances! surgical remo#al of the contralateral $reast may $e use as a form of cancer pre#ention in a $reast cancer patient who is at high ris+ for su$se(uently e#eloping cancer in her other $reast" The presence of lo$ular carcinoma in situ an $reast cancer family syn rome are two circumstances in which contralateral mastectomy may $e 5ustifie as a form of cancer pre#ention" Opera$ility an treatment ecisions must ta+e into account the patient-s me ical status an a$ility to tolerate the propose operation" Assessment of car iopulmonary status! hepatic an renal function! an nutritional status is #ital to etermining operati#e ris+ an to assessing nee s for hospital an home reha$ilitation"

An important $ut often un eremphasi'e goal of cancer management is restoring the patient-s physical! emotional! social! an employment status" The reha$ilitation for a woman with $reast cancer might $e irecte towar minimi'ing scarring an swelling of the tissues of the chest an arm! regaining strength an mo$ility in the shoul er after axillary lympha enectomy! an restoring contour an symmetry of the $reast" 4or some women an external prosthesis is satisfactory7 other women significantly $enefit from $reast reconstructi#e surgery" 6imilarly! patients with extremity sarcomas may $e consi ere can i ates for lim$ sal#age surgery or prosthesis use to maximi'e function .4ig" 9*9;0" 2ost patients expect to un erstan an participate in the ecision*ma+ing process! $ut many are confuse $y conflicting input from family! frien s! an e#en other physicians" Anxiety an uncertainty a$out the life*threatening nature of cancer an the prospects of physical isfigurement may ma+e it ifficult for them to un erstan treatment issues an to contri$ute to the ecision*ma+ing process" The physician shoul com$ine empathetic listening with a clear an comprehensi#e 90* to :0*minute iscussion of treatment options" The use of patient e ucation materials .written an #i eotape 0 an counseling $y nurses or physician assistants can facilitate the ecision* ma+ing process an increase the patient-s le#el of comfort an information a$out treatment planning" Clinical Diagnosis A complete history an physical examination is in ispensa$le $efore further 5u gments can $e ma e regar ing la$oratory testing an treatment" Common symptoms in the cancer patient may inclu e ysphagia! nausea! anorexia! #omiting! hematemesis! a$ ominal pain! melena! an hematoche'ia in patients with gastrointestinal cancer7 pro ucti#e cough an hemoptysis in lung cancer7 or an enlarging ten er mass in $reast an soft*part tumors" 6ymptoms generally correspon to the sites in#ol#e ! $ut nonspecific symptoms! such as night sweats an weight loss! may $e the initial manifestations of an un erlying neoplastic tumor" The uration of symptoms may in icate the aggressi#eness of the cancer or early case fin ing" The egree of physical impairment also influences treatment ecisions regar ing palliation" The patient-s past me ical history often len s clues to the iagnosis" Diethylstil$estrol hormone use $y the patient-s mother uring pregnancy! thymic irra iation for asthma! s+in irra iation for acne in chil hoo ! or a history of chronic inflammatory $owel isease are historical factors +nown to $e associate with the later e#elopment of cancer" The me ical history can also re#eal en#ironmental factors such as smo+ing! alcohol ingestion! or exposure to as$estos or aniline yes! which can $e relate to organ*specific sites of tumor e#elopment" A thorough me ical history pro#i es an important in ex of operati#e ris+ for the patient an me ications that may re(uire a 5ustment in their osage an fre(uency" In(uiry into family history may re#eal fin ings that support an initial iagnosis! suggest a itional associate lesions! or influence the extent of surgical treatment" A patient with a thyroi no ule may ha#e relati#es with episo ic hypertension! renal stones! or an Fa renal tumorG suggesting a multiple en ocrine neoplasia syn rome" A patient with relati#es who e#elope large*$owel cancer $efore the age of forty

shoul $e screene for polyposis syn romes" Aithout a thorough history! these an other genetically influence iseases will $e misse " Asymptomatic patients who are at high ris+ for e#elopment of certain types of cancer $y #irtue of age! family history! or personal history of isease shoul $e systematically screene " They shoul ha#e appropriate examinations as in icate ! using mammography! fecal occult $loo testing! flexi$le sigmoi oscopy! cer#ical cytology examination! etc"! as in icate " 6imple screening examinations! such as uterine cer#ical <ap smear an fecal occult $loo testing! shoul $e performe routinely" Often the surgeon is as+e to e#aluate a patient with a mass in a regional lymph no e area! such as the nec+! axilla! or groin" Usually this mass represents one or more lymph no es enlarge secon ary to an inflammatory process! originating in the area raine $y the regional no es" )ympha enitis is often multiple an ten er! an the primary area of inflammation is usually o$#ious" If the mass represents a solitary lymph no e or se#eral istinct enlarge painless no es with no o$#ious cause! the (uestion of $iopsy to iagnose cancer is raise " Open excisional $iopsy of lymph no es shoul $e eferre until a thorough search for the source of a primary tumor has $een ma e! $ut fine*nee le aspiration an cytology examination can $e one without causing regional tissue contamination with cancer cells" 3xcisional $iopsy of lymph no es containing metastatic cancer can release #ia$le cancer cells into the $iopsy woun $ecause efferent an afferent lymphatics containing such cells are i#i e in the process of excising the lymph no e" The incision of a no e or group of no es containing metastatic tumor may increase the ris+ of see ing the woun with cancer cells an #iolates the surgical principle of en $loc resection of the primary cancer! regional lymphatic channels! an regional lymph no es" Once neoplastic isease is growing free in connecti#e tissue an is no longer containe within the lymphatics or lymph no es! operati#e era ication of the tumor $ecomes ifficult $ecause the anatomic limits of the area containing cancerous tissue are $roa ene " If a enopathy is present in the hea an nec+ region! then the oral ca#ity! larynx! an pharynx shoul $e thoroughly in#estigate " If the mass is in the axilla or groin! the $reast an the s+in of the correspon ing extremity an portion of the trun+ shoul $e examine " The patient shoul $e (uerie a$out pre#ious remo#al of s+in lesions! particularly moles! that may represent melanoma" )a$oratory an Ra iologic 6tu ies In a ition to the routine la$oratory tests such as complete $loo count! coagulation profile! multichannel serum $iochemistry profile! an chest x* ray! other stu ies are useful in etermining the prognosis in patients with malignant isease .Ta$le 9*/90" 3#aluation of the patient with a suspicious $reast lesion shoul inclu e $ilateral mammography" Roentgenographic characteristics may support the clinical iagnosis an re#eal occult lesions in the contralateral $reast" Clinically occult lesions may un ergo mammographically irecte stereotaxic nee le $iopsy or nee le locali'ation for open $iopsy" The patient with $reast cancer who has a$normal li#er function tests or palpa$le hepatomegaly shoul un ergo a CT scan7 those with s+eletal symptoms shoul recei#e a ra ionucli e technetium 99m $one scan" 2etastatic lesions / cm or more in iameter can $e etecte in the li#er using unenhance an enhance CT scans with :E& mm slices"

<atients who ha#e symptoms or signs attri$uta$le to the gastrointestinal tract shoul recei#e an air contrast upper or lower $arium stu y" Air contrast $arium stu ies show greater mucosal etail than $arium stu ies without air contrast an are more sensiti#e to small lesions" 3n oscopy can also $e use for $oth iagnosis an tissue examination" CT scans of the chest are useful in e#aluating suspicious lesions note on chest x*ray an s+eletal an soft tissue lesions" Ultrasoun an CT scanning can $e particularly useful in the etection of hepato$iliary cancer" In#asion of #ascular structures an ilate extrahepatic an intrahepatic ucts secon ary to extrahepatic $iliary o$struction $y a neoplasm can $e emonstrate " Coexisting ascites also may $e note " 2agnetic resonance imaging is #alua$le in etermining the location an extent of soft tissue an $one tumors an their relationship to a 5acent structures" Dy (uantitati#e imaging! the physical characteristics of tumors often can $e etermine " 6erum mar+ers! such as carcinoem$ryonic antigen .C3A0! CA/9*9! $eta* human chorionic gona otropin .$eta*1C=0! an alpha*fetoprotein .A4<0 are useful in the management of patients with specific tumors .Ta$le 9*900" C3A is a tumor*associate glycoprotein foun in se#eral ifferent soli tumors such as $reast! lung! gynecologic! an gastrointestinal cancers an sarcomas" <lasma C3A le#els are not sensiti#e or specific enough to $e of great #alue in screening for cancer! particularly for early lesions" 3le#ate plasma le#els are correlate with increasing tumor si'e! stage! an the extent of positi#e lymph no e metastases in patients with large*$owel cancer" Ahen surgical remo#al of the primary tumor is complete! measuring circulating C3A le#els may $e useful uring the follow*up perio as an early mar+er of recurrent systemic isease" 6urgical <athology The importance of accurate pathologic iagnosis in the proper surgical treatment of cancer patients cannot $e o#erstate " Determinations of the presence of cancer! the histologic gra e! the site of the primary or metastatic foci! an surgical resection margins pro#i e critical information" 4ine*nee le aspiration cytology of a soli lesion can $e performe with a 99*9&*gauge nee le to assess the cytology of palpa$le tumors" Diagnosis using fine*nee le aspiration techni(ues concurs with surgical pathologic iagnosis in 9% percent of teste lymph no es an %% percent of $reast tumors examine " This techni(ue is rapi ! minimally traumatic! an highly accurate for iagnosis of a clearly palpa$le mass or a ra iographically #isi$le lesion .4ig" 9*9&0" 4alse*positi#e results are rare7 false*negati#e results may occur $ecause of small sample si'e! site of the lesion! egree of tissue necrosis! an tumor type" Aith the use of fine*nee le aspiration techni(ues in com$ination with roentgenography an ultrasonography! eep! nonpalpa$le lesions are amena$le to iagnosis with minimal mor$i ity! e"g"! transthoracic aspiration of lung no ules using CT scan an CT* irecte aspiration of pancreatic masses" 4ine*nee le aspiration cytology is particularly useful in the iagnosis of palpa$le masses in the $reast an thyroi ! as well as palpa$le suspicious no es in the nec+! axilla! or groin" Aspiration cytology cannot $e completely epen e on for gra ing of soli tumors! for su$ i#i ing types of lymphoma! or for accurate iagnosis after ra iation treatment! $ut a positi#e iagnosis greatly facilitates iagnostic an treatment

planning" Use of immunohistochemical mar+ers may $e of a itional iagnostic #alue .Ta$le 9*9/0" Ahen an accurate iagnosis of tumor type an gra e is necessary! an incisional or excisional $iopsy is re(uire " Care shoul $e ta+en in the planning of a surgical $iopsy so as not to 5eopar i'e later surgical extirpation or the use of s+in flaps" In general! large soft*tissue lesions .& to % cm0 that are eeper than the superficial fascia are $est sample $y incisional $iopsy .4ig" 9*9@0" 6mall .O9 cm0 superficial lesions can $e manage $y excisional $iopsy with a #iew towar further treatment epen ing on tumor type! gra e! an epth of in#asion" 4ro'en section iagnosis shoul not $e relie on to pro#i e histologic gra e of the tumor an information a$out epth of in#asion" 6urgical margins of resection can an shoul $e e#aluate $y fro'en section examination" In some instances! such as malignant rectal polyps! local excisional therapy is all that is re(uire if permanent histopathology etermines only superficial in#asion! a e(uate resection margins! low*gra e ifferentiation! an a$sence of #ascular or lymphatic in#asion" Decision for Operation A ecision for curati#e operation presupposes that the tumor is locali'e or confine regionally! that the area of the tumor can $e encompasse $y regional excision! that e#i ence of istant metastases cannot $e foun ! an that the tumor is appropriately treate $y operation" =i#en a ecision for a curati#e operation! the extent of the surgical proce ure must $e efine " In principle! an en $loc resection shoul $e performe ! encompassing the primary tumor! regional lymph no es! an inter#ening lymphatic channels" This principle is perhaps $est illustrate $y operations for large*$owel cancer! in which the regional lymphatics of the colon .$ut not the rectum0 course in one irection with the ma5or arteries an #eins" This principle is less applica$le in the rectum! where lateral sprea an the limiting confines of the lateral pel#ic wall may preclu e a wi e margin" 6imilarly! the principle is less applica$le for $reast cancer! for which multiple pathways of lymphatic sprea are well recogni'e .e"g"! internal mammary an retropectoral no es! axillary an supracla#icular no es0" As a result of these #aria$les! an partly ue to emergence of earlier stage isease! the extent of #arious operations for cancer is un ergoing change" This Fremo elingG is $est illustrate in $reast cancer! for which the tren is towar local excision of the primary tumor with ra iation therapy an a 5u#ant chemotherapy" The therapeutic #alue of regional no e issection has $een (uestione $y some" <erforme properly! it is of clear prognostic #alue an coul esta$lish the ata$ase for precise staging for other a 5u#ant treatments" 6urgical proce ures may $e performe solely for staging purposes" An example is staging laparotomy in 1o g+in-s isease! in which multiple lymph no e $iopsies! li#er an $one marrow $iopsies! an splenectomy are performe " In a #ariety of settings! operati#e inter#ention is use for palliati#e treatment" Dypasses are performe aroun o$structe #iscera! an gastro5e5unostomy is one for o$structing carcinoma of the stomach" Chole ocho uo enostomy or 5e5unostomy proce ures are use as $ypass proce ures for periampullary carcinoma of the pancreas o$structing the common $ile uct" Intraluminal stent tu$es may $e inserte through an o$structing esophageal

carcinoma to allow the patient to ta+e oral nourishment! an colon i#ersion .$ypass or colostomy0 may $e performe for o$structing large*$owel cancer" The use of cytore ucti#e surgery is contro#ersial" This approach may $e most rele#ant in o#arian cancer! for which eli$erate remo#al of as much o#arian tumor as possi$le may enhance the patient-s response to su$se(uent chemotherapy or ra iation therapy" Cytore ucti#e operations also may $e #ali in the treatment of some chil hoo tumors! such as neuro$lastoma" Rarely is cytore ucti#e surgery .F e$ul+ingG0 applica$le in other circumstances" The extent of an operation shoul $e ictate $y precise staging" Aith precise staging! an with the presence of effecti#e chemotherapy! operati#e inter#ention may $e more limite " 4or example! the tra itional management of non*seminoma germ cell tumor of the testis has $een ra ical orchiectomy an retroperitoneal lymph no e issection exten ing to the renal #asculature" The pre icta$ility of normal le#els of $*1C= an A4< with normal CT scans an ultrasoun ! $ac+e $y effecti#e chemotherapy shoul issemination occur! now may permit only ra ical orchiectomy without no e issection in those patients who are normal $y these eterminants" This approach results in fewer patients suffering a #erse conse(uences from retroperitoneal no e issection an resultant ner#e amage with impotence an retrogra e e5aculation" 2ore precise pretreatment planning of tumors tra itionally treate $y operation is a main o$5ecti#e of current research" Research in areas such as lymphoscintigraphy an the use of ra iola$ele monoclonal anti$o ies is $eing explore to achie#e greater precision of staging" <reoperati#e <reparation Appropriate preoperati#e preparation inclu es +nowle ge of the natural history of the patient-s isease! e#aluation of operati#e ris+! ecisions rele#ant to the nee for an timing of operati#e inter#ention! estimate of the physiologic stress potentially impose $y the operation! an the (uantitati#e assessment of the patient-s physiologic status" Comprehensi#e preparation of a patient for operati#e therapy re(uires $oth physiologic an psychologic support" In the preoperati#e preparation of the surgical patient! the physician shoul consi er potential a$normalities such as aci *$ase isor ers! malnutrition! infection! respiratory insufficiency! hepatic an renal ysfunction! anemia! an clotting a$normalities" The ma5or aims of preoperati#e therapy shoul $e to prepare the patient to withstan the stresses of operati#e therapy an to minimi'e the ris+s of the surgical proce ure" The appropriate uration of the preoperati#e perio epen s on the urgency of the operati#e proce ure" The length of time feasi$le for correction of preexisting eficits may $e short .hours0! as in the case of massi#e gastrointestinal hemorrhage or free perforation of an o$structe colon7 interme iate! as in complete $ut nonstrangulate $owel o$struction7 or prolonge . ays0! as in 5aun ice ue to pancreatic carcinoma" Determination of the urgency of a particular operati#e proce ure re(uires +nowle ge of the operati#e ris+ an the natural history of the isease without imme iate operati#e inter#ention" Inclu e in this e#aluation are factors such as the age of the patient .chronologic an physiologic0! egree of physiologic erangements an nutritional eficits! presence of organ system failure or insufficiency! an stage of the primary isease" Although the urgency of operati#e inter#ention may limit the length of preoperati#e preparation an the metho s a#aila$le for correcting preexisting

a$normalities! partial repair of eficiencies shoul $e initiate promptly with plans ma e for more complete correction uring an after operati#e therapy" 2onths of chronic un ernutrition cannot $e correcte in a matter of hours! $ut anemia! ehy ration! an electrolyte a$normalities can $e ameliorate $y early initiation of intensi#e intra#enous support! gui e $y appropriate la$oratory monitoring" Anemia is common among patients with cancer an shoul $e correcte with pac+e re cell transfusions to a hematocrit le#el of :0 percent or more $efore ma5or operati#e inter#ention when much $lee ing is anticipate " Ahen possi$le! patients shoul auto onate one or two units of $loo within ; wee+s of surgery to ecrease the ris+ of #iral transmission from nonautologous $loo transfusions" Clotting a$normalities can usually $e etermine $y an a e(uate patient history! physical examination for e#i ence of hemostatic pro$lems! an routine la$oratory in#estigation .prothrom$in time! partial throm$oplastin time! an platelet count0" Ascertainment of rug ingestion .especially aspirin! phenyl$uta'one! or in omethacin0 is important $ecause some me ications result in (ualitati#e platelet eficiencies! lea ing to serious clotting a$normalities" Aspirin ingestion shoul $e a#oi e for at least / wee+ $efore electi#e hospital a mission" 6ome me ical con itions are also associate with platelet ysfunction! such as uremia! leu+emia! an hepatic failure" The template $lee ing time is a useful screening test for patients with suspecte platelet ysfunction" It is generally agree that a count of &0!000Nmm: functionally acti#e platelets is sufficient for ma5or operati#e proce ures" After ma5or electi#e operations! woun infection rates ha#e #arie from 0"& percent to 90 percent epen ing on whether the proce ure was FcleanG or Fcontaminate G .Ta$le 9*990" Desi es the a e mor$i ity an potential mortality! surgical infection increases the a#erage uration of hospitali'ation $y at least /0 ays! resulting in a large increase in hospital costs" Resistance to infection .immune function0! ose an #irulence of the in#a ing $acteria! an the presence of foreign $o y! ea tissue! or anaero$ic con itions are all factors that etermine the pro$a$ility of woun infection" Anti$iotic prophylaxis is use to re uce the inci ence of postoperati#e woun infection in patients un ergoing contaminate operations" Chemoprophylaxis is useful to cancer patients who are un ergoing hea an nec+ surgery! chest surgery! a$ ominal gastrointestinal surgery! an pel#ic surgery! such as hysterectomy" The use of anti$iotics in these situations shoul $e8 ./0 time to allow a e(uate woun anti$iotic le#els $efore contamination7 .90 a ministere only for a short time uring the perioperati#e perio 7 .:0 specific for the most li+ely infecting organism.s07 an .;0 safe! i"e"! it shoul present minimal a itional ha'ar to the patient" Cancer Operations )ocal Resection Ai e local resection that remo#es an a e(uate margin of normal tissue with the tumor mass may $e a e(uate for certain low*gra e neoplasms that o not metastasi'e to regional no es or wi ely infiltrate a 5acent tissues" Dasal cell carcinomas! thin melanomas .i"e"! less than /"0 mm0! an mixe tumors of the paroti glan are

examples of such neoplasms" 6ome normal tissue surroun ing the tumor shoul $e excise to pre#ent local recurrence" Ra ical )ocal Resection Neoplasms! such as soft tissue sarcomas an esophageal an gastric carcinomas! may sprea wi ely $y infiltration into a 5acent tissues" In such cases it is necessary to remo#e a wi e margin of normal tissue with the neoplasm" The wi e margin of normal tissue $etween the line of excision an the tumor mass also acts as a protecti#e $arrier against tumor cell spill into the se#ere lymph an $loo #essels" The greater the wi th of normal tissues $etween the plane of issection an the tumor! the greater the li+elihoo of a complete local excision" If the tumor was pre#iously explore ! $ut not remo#e ! or if an incisional $iopsy proce ure was performe ! a segment of s+in an the un erlying muscles! fat! an fascia must $e remo#e far $eyon the limits of the original incision $ecause tumor cells may ha#e $een implante in the incision uring the initial operation" 2alignant neoplasms are not well encapsulate " A pseu ocapsule compose of a compression 'one of neoplastic cells may surroun the tumor" This apparent encapsulation offers a great temptation for simple enucleation! $ecause the tumor may $e easily islo ge from its $e " The surgeon must cut through normal tissue at all times an shoul ne#er isrupt the neoplasm uring its remo#al" Dissection shoul procee with meticulous care to a#oi tumor cell spill" The surgeon shoul resect as far as possi$le from the gross extent of the tumor on all si es! inclu ing the eep aspect" 6+in! su$cutaneous fat! an some muscles may ha#e to $e sacrifice ! $ut usually this causes little functional loss" 6acrifice of tumor* in#ol#e ma5or #essels! ner#es! 5oints! or $ones may $e necessary to o$tain a curati#e result" The extent of operation is also etermine $y functional integrity" Ra ical Resection with 3n Dloc 3xcision of )ymphatics 6ince many neoplasms commonly metastasi'e $y way of the lymphatics! operations ha#e $een esigne to remo#e the primary neoplasm an the regional lymph no es raining that area in continuity with all the inter#ening tissues" Con itions are $est for this type of operation when the collecting no es of the lymphatic channels raining the neoplasm lie a 5acent to the primary site or when there is a single a#enue of lymphatic rainage that can $e remo#e without sacrificing #ital structures" It is important to a#oi cutting across in#ol#e lymphatic channels $ecause such action can increase the possi$ility of local isease recurrence" 3n $loc regional lymph no e issections such as those un erta+en in mo ifie ra ical mastectomy an ra ical total gastrectomy shoul $e performe when there is clinical in#ol#ement of lymph no es $y metastatic tumor" In many cases the tumor has alrea y sprea $eyon the regional no es! an the li+elihoo of cure after such proce ures may $e (uite low" 3n $loc remo#al of the in#ol#e no es offers the only chance for cure an pro#i es significant palliation an local control" )ympha enectomy There are some general principles common to lymph no e issection .)ND0 at #arious anatomic sites! particularly the nec+! axilla! an groin .4ig" 9*9%0"

./0 The surgeon must thoroughly un erstan the anatomy of the lymph no es in each area of the $o y an shoul incorporate all the raining no es at ris+ into the surgical specimen" .90 The goals of )ND must $e clearly efine as cure! local isease control .i"e"! palliation0! an Nor staging" )ND may $e curati#e in some patients with $ul+y no al metastases! or palliati#e in certain patients with large! symptomatic no al metastases in the presence of istant metastases" 6taging to etermine whether metastatic isease is present in the regional lymph no es will assume increase importance with the a#aila$ility of effecti#e a 5u#ant therapies" .:0 An incomplete )ND is generally not accepta$le except when the goals of surgery are strictly palliati#e" Ahen the intent is curati#e! as in a patient with regional metastases from a primary cutaneous melanoma! complete )ND is #ital" Dut a partial axillary issection .le#els I an II0 is satisfactory for $reast cancer! $ecause the goals are staging an local isease control" .;0 The incision pro#i ing access to the un erlying regional no es shoul $e place to minimi'e the ris+ of i#i ing lymphatic #essels that coul contain malignant cells" .&0 4or issections of lymph no es in the nec+! axilla! or groin! close * suction catheter rains are important to e#acuate $loo an serum an +eep the tissues in apposition! minimi'ing the ris+ of seroma formation" One or two large catheters may $e inserte percutaneously through the lower flap an place in a epen ent part of the woun " Although there are no o$5ecti#e ata on the $est time to remo#e these e#ices! the inci ence of seroma formation increases if they are remo#e too early! an the inci ence of woun infection increases if they are +ept in too long .especially longer than /0 ays0" Catheters pro$a$ly shoul $e remo#e when the rainage is less than ;0 m) per 9; h! or ? ays after surgery! whiche#er comes first" .@0 The use of prophylactic anti$iotics is contro#ersial" The inci ence of woun infection is highest after a groin issection an lowest after a nec+ issection" 6taphylococci an streptococci are the most common organisms isolate from these woun infections" The use of prophylactic anti$iotics is pro$a$ly 5ustifie on an empirical $asis for groin an axillary lympha enectomies! $ut this must $e confirme with controlle clinical trials" .%0 In patients with $ul+y no al metastases! especially with in#asion an fixation into surroun ing tissues! such as in the axilla for metastatic $reast cancer an in the nec+ for metastatic melanoma! the ris+ of regional recurrence is greater than 90 percent" Data from prospecti#e clinical trials in icate that a 5u#ant ra iotherapy might $e consi ere to impro#e regional isease control" 3lecti#e )ymph No e Dissection .)ND0 The high rate of local cancer recurrence after surgical resection when lymph no es are grossly in#ol#e an the high error rate when palpation is use to assess the extent of the in#ol#ement ha#e le to electi#e or prophylactic issection of clinically normal regional lymph no es close to the primary tumor" 2icroscopic examination of these excise lymph no es re#eals e#i ence of tumor sprea in 90 to ;0 percent of carcinomas an melanomas" A higher &*year sur#i#al rate was reporte for patients

un ergoing excision of lymph no es with microscopic rather than clinically e#i ent tumor in#ol#ement" This concept of electi#e )ND has $een challenge $ecause it is not clear whether cure rates are impro#e if the no es are remo#e $efore they are palpa$le" Controlle clinical trials irecte towar this (uestion in many types of neoplasms are currently un er way" Regar less of irect therapeutic $enefit! fore+nowle ge of tumor in regional no es can affect staging! treatment! an prognosis" 4or example! patients with $reast cancer who ha#e metastases to regional no es may $enefit consi era$ly from a 5u#ant chemotherapy or hormonal therapy" Also some patients with eep melanomas .P ; mm0 may $ecome can i ates for in#estigational a 5u#ant trials only if lymph no e metastases are present" 4urthermore! a comparison of experimental results from ifferent institutions epen s on accurate staging when therapy is initiate " 6electi#e )ymph No e Dissection 2orton an colleagues recently escri$e a promising techni(ue for etection of the regional raining lymph no es most li+ely to contain metastatic tumor cells sprea ing from a primary cutaneous melanoma" Their techni(ue of intraoperati#e lymphatic mapping an selecti#e sentinel )ND is currently un er in#estigation in a phase III multicenter trial for melanoma an is also $eing applie to $reast carcinoma an other neoplasms" Initially the techni(ue relie on in5ection of a #ital $lue ye at the tumor site an #isual trac+ing of this ye along the lymphatics to the no al $asin" 6entinel no e mapping has $een facilitate $y a ing a ra iola$ele isotope to the ye an monitoring its path $y a han hel gamma pro$e" 3xtensi#e 6urgical <roce ures 6ome slow*growing primary tumors can reach enormous si'e an may locally infiltrate wi ely without the e#elopment of istant metastases" Ra ical operati#e proce ures can $e un erta+en for these extensi#e an nearly inopera$le tumors! with occasional cure" A #ances in surgical techni(ues! anesthesia! physiologic monitoring! an supporti#e care .$loo transfusions! anti$iotics! an flui an electrolyte management0 ha#e permitte the e#elopment of more ra ical an extensi#e operati#e proce ures that ha#e significantly impro#e the local control rates for certain neoplasms" These extensi#e surgical proce ures sometimes offer a chance for a cure that is not possi$le $y other means an are 5ustifie in selecte situations when extensi#e la$oratory wor+up shows no e#i ence of istant metastases" These operations shoul $e un erta+en only $y experience surgeons who can select those patients most li+ely to $enefit" The surgeon consi ering extensi#e proce ures such as pel#ic exenteration! hemipel#ectomy! fore(uarter amputation! or ra ical operations for hea an nec+ carcinomas must $e willing to accept the responsi$ility for the patient-s postoperati#e emotional reha$ilitation" <el#ic exenteration is a well*concei#e operation capa$le of curing patients with ra iation*treate recurrent cancer of the cer#ix an certain well* ifferentiate an locally extensi#e a enocarcinomas of the rectum" This operation remo#es the pel#ic organs .$la er! uterus! an rectum0 an all soft tissues within the pel#is" Dowel function is restore with colostomy" Urinary tract rainage is esta$lishe $y anastomosis of ureters into a segment of $owel .ileum or sigmoi colon0" The &*year relapse*free sur#i#al after pel#ic exenteration is 9& percent"

1emipel#ectomy .resection of the lower extremity an iliac $one0 can sometimes $e curati#e for s+eletal sarcomas limite to the hea of the femur or aceta$ulum or to one*half of the pel#ic structures an for some slow*growing soft tissue sarcomas of the upper thigh an $uttoc+ that recur locally $ut metastasi'e slowly" 4ore(uarter amputation .resection of the upper extremity an scapula0 can offer similar results when the neoplasm is limite to the $ones of the scapula an upper humerus or to the soft tissues of the shoul er gir le" 6urgery of Recurrent Cancer 6urgical resection of locali'e ! recurrent! low*gra e! slow*growing malignancies may pro uce a long perio of remission" 6urgical proce ures are fre(uently successful in controlling recurrent soft tissue sarcomas! anastomotic recurrences of colon cancer! certain $asal an s(uamous cell carcinomas of s+in! an $reast cancer recurring after lumpectomy" 1owe#er! surgical resection of the recurrent neoplasm in the patient with metastatic isease is usually unsuccessful an rarely in icate ! unless the entire tumor mass can $e completely remo#e " The results of routine secon *loo+ operations to etect early recurrence of colon cancer ha#e not $een impressi#e! $ut tumor mar+ers! such as C3A! ha#e $een extremely useful for selecting patients most li+ely to $enefit from reoperation" In general! a local recurrence can $e treate surgically or with ra iation" The surgeon must eci e which form of treatment will achie#e local control with the lowest mor$i ity" 6pecific Organs Dreast In the Unite 6tates $reast cancer is the most common malignancy in women an secon only to lung cancer in cancer*relate mortality in women" In /99& more than /?0!000 women were iagnose with in#asi#e $reast cancer! an the pro$a$ility of a woman-s e#eloping $reast cancer at some point uring her life was estimate at / in 9" The increase inci ence of $reast cancer has increase awareness of the isease" 6creening mammography is use more commonly! $ecause clear $enefit has $een shown in large prospecti#e stu ies of women o#er the age of &0 years" The $enefit has occurre in iagnosing more malignancies at in situ or early stages compare with women who are self* iagnose an those outsi e of screening programs" Aomen shoul $e screene for $reast cancer with a $aseline mammogram $etween the ages of :0 an ;0 years! a mammogram e#ery two years $etween ages of ;0 an &0 years! an yearly thereafter" 3 ucation regar ing $reast self*examination an time physical examinations $y a physician shoul also $e one" In FearlyG cases! a woman presents to the physician with an Fa$normalG mammogram showing microcalcifications! asymmetry! a mass with or without s+in thic+ening! or other signs of potential malignancy" Alternati#ely! the patient may present with a palpa$le $reast mass! nipple ischarge! or signs of more a #ance isease such as s+in retraction or inflammatory s+in changes" <hysical examination shoul $e carrie out to loo+ for local regional metastases"

A iagnostic algorithm may $e e#elope ! etermine $y the primary site an si'e of the suspicious lesion" <alpa$le lesions initially may $e iagnose $y fine*nee le aspiration in the outpatient setting" If this cytologic examination is positi#e! there shoul $e a thorough iscussion with the patient of treatment options an efiniti#e therapy initiate " In cases in which a $reast*conser#ing proce ure can $e one! the primary lesion is excise ! with pathologic confirmation of the a e(uacy of tumor margins! an tumor tissue is prepare for estrogen an progesterone receptors" A limite axillary issection is performe at that time! with the entire proce ure one un er general anesthesia" In the case of an e(ui#ocal or non iagnostic fine*nee le aspiration! the $reast mass can $e excise un er local anesthesia with a margin of normal $reast tissue .fro'en section is one for iagnosis an tissue is processe for hormone receptors0" The axillary issection can $e one at a su$se(uent ate" If the lesion is not palpa$le $ut is mammographically efine ! a nee le locali'e $iopsy or stereotactic core nee le $iopsy is one for iagnosis" The responsi$ility of the surgeon is to pro#i e the patient with the $est chance for cure! for local chest wall control of tumor! an for minimal mor$i ity" If axillary lymph no es are not clinically palpa$le! issection of the lateral axilla .le#el I an II lymph no es0 is performe ! with the lateral $or er of the pectoralis minor muscle as the me ial limit of the issection" The management of these patients has e#ol#e towar $reast conser#ation surgery .lumpectomy! axillary issection! an $reast irra iation0" This coinci es with the tren towar smaller cancers associate with greater pu$lic awareness an increase use of $reast screening using physical examination an mammography" In patients with larger primary tumors .P;E& cm0 or those who ha#e high*ris+ features that might compromise local control! a mo ifie ra ical mastectomy with or without primary reconstruction can $e one" In the past! there was greater emphasis on irra iation of lymph no e regions .internal mammary no es! supracla#icular no es0! $ut the long* term sur#i#al $enefit of a 5u#ant ra iation therapy has not $een shown" Other approaches ha#e $een use to treat patients with small .O9 cm0 cancers of the $reast" Ceronesi an associates ./9?/0 compare ra ical mastectomy with (ua rantectomy! axillary issection! an ra iotherapy in %0/ patients with $reast cancers measuring less than 9 cm in iameter" )ocal chest wall or ipsilateral $reast recurrences an patient actuarial sur#i#al were similar in $oth groups" In the National 6urgical A 5u#ant Dreast an Dowel <ro5ect .N6AD<0 trials! 4isher an colleagues ./9?90 reporte that among patients with negati#e no es! /9 percent of those who un erwent irra iation an :% percent of those who i not un ergo irra iation ha#e a recurrence of $reast tumor uring the ? years of follow*up .p O " 00/0" The pro$a$ility of a recurrence in those with positi#e no es .all of whom recei#e chemotherapy0 was only @ percent with irra iation an ;: percent with no irra iation" Irra iation of the $reast o$#iously is important to ecrease local recurrence an the nee for su$se(uent mastectomy" In situ intra uctal or lo$ular $reast cancer is sel om associate with lymph no e metastases" In situ uctal $reast cancer may $e treate $y local excision with or without ra iation therapy or $y total mastectomy with imme iate reconstruction" The choice of therapy is often ictate $y the extent of the in situ isease! the presence or

a$sence of multifocal lesions! the histologic type! the patient-s esires regar ing treatment! cosmesis! an future ris+" 6ixty percent of recurrent $reast cancer occurs within two years after mastectomy" If the initial local treatment for $reast cancer is a e(uate! local chest wall recurrence rates shoul $e less than & percent in stage I isease an less than /0 percent in stage II isease" Dreast reconstruction can $e performe simultaneously with mastectomy in women with in#asi#e $reast cancer" The ma5or criticism of $reast reconstruction is the potential for elay in iagnosing local chest wall recurrence! $ut this ris+ is small" The $est efine role for imme iate $reast reconstruction may $e in the treatment of in situ $reast cancer" 3sophagus an 6tomach Operati#e therapy for carcinomas of the esophagus has $een associate with su$stantial mor$i ity attri$ute to patient factors! such as preexisting car iopulmonary isor ers an malnutrition! an to anatomic factors! such as the location of the primary tumor an the local! regional! an lymphatic sprea " In a ition to intensi#e preoperati#e nutritional an pulmonary support to re uce postoperati#e complications! a 5uncti#e ra iotherapy an Nor chemotherapy ha#e $een a ministere in an attempt to re uce local recurrence an increase patient sur#i#al" Ran omi'e trials with preoperati#e irra iation alone ha#e not shown sur#i#al $enefit" <reoperati#e com$ination chemotherapy! consisting of cisplatin! $leomycin! an #in esine! results in tumor shrin+age in nearly half of all patients" In a ition! the surgical resecta$ility rate is increase in patients gi#en preoperati#e chemotherapy an ra iation treatment" In the e#ent that resection for cure is impossi$le! resection of the tumor for palliation shoul $e performe " If a patient can ingest a e(uate nutrients $y mouth! the (uality of remaining life is impro#e an the opportunity for further palliation from chemotherapy an ra iation therapy is increase " In patients with large tumors! surgical palliation may inclu e $ypass $y colon interposition" The ris+ of pro ucing a ma5or postoperati#e complication $y oing a palliati#e resection must $e weighe against the potential $enefits" The operating surgeon must consi er life expectancy an (uality of remaining life in eci ing $etween palliati#e resection or $ypass an nonoperati#e treatment" The surgical treatment of gastric cancer is $ase mainly on operati#e an pathologic o$ser#ations" Carcinoma of the istal portion of the stomach .restricte to pylorus an antrum0 shoul $e treate $y su$total gastrectomy! omentectomy! an remo#al of su$pyloric! hepatic arterial! an preaortic lymph no es" Tumors locate in the $o y of the stomach ha#e $een treate $y su$total or total gastrectomy with the choice $ase on tumor location7 little ifference in o#erall sur#i#al rate is note $etween these two proce ures" <ancreas If e#i ence of istant or regional metastases from carcinoma of the pancreas or periampullary region cannot $e i entifie ! the patient in goo me ical con ition is a

can i ate for pancreatico uo enectomy .see Chap" :00" The malnourishe patient shoul recei#e either enteral or parenteral nutritional support uring preoperati#e preparation! unless eteriorating li#er function secon ary to $iliary o$struction necessitates imme iate $iliary ecompression" 3le#ate le#els of serum $iliru$in an al+aline phosphatase in a well*nourishe patient with normal hepatocellular function are not $y themsel#es contrain ications to surgery" )i#er A #ances in anesthesia! $loo replacement! an surgical techni(ue ha#e ma e ma5or hepatic resection feasi$le with low mortality" <atients with primary hepatoma an certain solitary metastatic cancers! e"g"! from carcinoma of the colon! shoul $e e#aluate for possi$le curati#e resection" 1epatic ultrasoun or a$ ominal CT scanning com$ine with plasma A4< an C3A le#els are the most effecti#e tests for screening patients for li#er isease! $ut their sensiti#ity is limite " Arteriography outlines the arterial $loo supply to the li#er" CT an intraoperati#e ultrasonography are sensiti#e tests that i entify small metastatic eposits an can etect tumor in the lateral segment of the left hepatic lo$e" At exploration! metastases limite to one hepatic lo$e shoul $e consi ere for resection either $y we ge excision or lo$ectomy" If the cancer is unresecta$le! hepatic arterial e#asculari'ation an Nor chemotherapy infusion may $e performe " )arge Dowel <reoperati#e preparation of the patient with colorectal carcinoma re(uires thorough assessment $y physical examination! ra iographic metho s! an en oscopic techni(ues to etermine the si'e! mo$ility! an histology of the primary tumor" 6ynchronous cancers of the large $owel are note in approximately ; percent of patients" In the a$sence of o$struction! all patients shoul un ergo a thorough mechanical $owel preparation with laxati#es an enemas preoperati#ely" Oral neomycin an erythromycin is one anti$iotic prophylactic regimen that is use along with mechanical $owel preparation on the ay $efore operation to re uce intraluminal $acterial content" In colonic resection! the mesentery of the cancer*$earing $owel shoul $e remo#e as completely as possi$le to a#oi local recurrence an o$tain a e(uate lymph no e remo#al for staging an attempte surgical cure" =oo surgical 5u gment is necessary when operating on any part of the colon! $ut it is re(uire most when ealing with carcinoma of the rectum an rectosigmoi " The surgeon shoul pro#i e a com$ination of the $est opportunity for cure an local control of isease with the least chance of postoperati#e mor$i ity! mortality! an loss of function" 6phincter*sa#ing proce ures shoul $e performe if the chance for local control is not 5eopar i'e " Cancerous lesions within 9 cm of the anal #erge that in#a e through the muscularis propria .T:0 usually shoul $e remo#e $y a$ ominoperineal resection" A tumor cephala to this le#el often can $e manage with a low anterior resection or pull*through proce ure" <reoperati#e ra iation therapy with chemotherapy may $e helpful to permit tumor shrin+age! estroy peripheral tumor micrometastases! an allow a sphincter*sparing proce ure"

)ocal excision can $e one for early cancer of the rectum in lesions that un ergo complete excision with low*gra e histology an with tumor confine to the su$mucosal plane of the $owel wall without lymphatic or #ascular in#asion" This approach is prefera$le to electrosurgical iathermy! which estroys histologic mar+ings an ma+es staging impossi$le" 3lectrocoagulation is useful as palliation for selecte patients" A 5uncti#e ra iation an chemotherapy treatment may $e in icate $ecause surgical therapy alone yiel s high recurrence rates in Du+e-s C lesions with high* gra e histology! si'e greater than ; cm! an istance within & cm of the entate line compare with other rectal tumors" <reoperati#e ra iotherapy an chemotherapy com$inations may increase resecta$ility! pre#ent see ing! an estroy cancer cells outsi e the operati#e fiel " <ostoperati#e ra iotherapy FsparesG those patients with more fa#ora$le pathologic lesions an can $e gi#en to a surgically F efine G area! $ut complications such as small $owel ra iation enteritis are more fre(uent" 2elanoma Treatment of malignant melanoma is $ase on epth of s+in in#asion! location on the $o y! an areas of potential metastatic sprea " <unch $iopsy may $e satisfactory for histologic iagnosis! $ut excisional $iopsy! inclu ing a small amount of su$cutaneous fat! is prefera$le in or er for the pathologist to efine accurately the epth of in#asion an tumor thic+ness" <athologic staging shoul $e one on permanent sections! $ecause interpretation of fro'en*section preparations can $e mislea ing" Thin! ra ial growth phase melanoma that has not penetrate through the papillary ermis .Clar+-s le#els I an II0 or is less than 0"%@ mm thic+ sel om metastasi'es or recurs locally an has a 9& percent chance of initial cure $y a e(uate local excision" A e(uate local excision usually can $e achie#e $y wi e excision of the $iopsy scar with / cm margins sufficient to allow primary closure of the woun " 6ome lesions! particularly the superficial sprea ing type! may $e too large for excision an primary closure! an flap rotation or s+in grafting may $e necessary" 6imilarly! s+in grafts may $e nee e in areas of the $o y where s+in is not easily mo$ili'e ! e"g"! the sole of the foot" Thic+ #ertical growth phase lesions that ha#e penetrate to the reticular ermis .le#el III0! into the reticular ermis .le#el IC0! or through it an into the su$cutaneous fat .le#el C0 ha#e a much higher potential for metastasis" This ris+ is irectly proportional to the epth of in#asion .especially when greater than /"& mm in thic+ness0 an to the location on the $o y .the ris+ in hea an nec+ tumors is greater than that in trun+ tumors! which is greater than that in tumors of the extremities0" All regional no e*$earing areas an the area $etween the primary melanoma an the regional lymph no es shoul $e carefully e#aluate for clinical regional lymph no e metastases or in*transit metastases coursing to the regional lymph no es through the intra ermal or su$ ermal lymphatics" 6urgical treatment of all thic+ ./"& to 9 mm0 melanomas must $e irecte to era ication of the primary tumor! areas of potential in*transit metastases! an the regional lymph no e*$earing areas" Treatment of the primary lesion shoul inclu e a wi e excision with / cm margins" Treatment of regional lymph no es also must $e practical" A thic+ melanoma in the mi le of the trun+ may potentially metastasi'e to

the axillary! inguinal! or supracla#icular lymph no e areas on either si e7 prophylactic lymph no e issection of each of these locations woul $e impractical" A ult 6oft Tissue 6oft tissue sarcomas in a ults may grow to a large si'e without etection! as they are often eeply situate " <rognosis has $een shown to $e correlate with tumor si'e! site! histologic type! an egree of ifferentiation" Tumors that are small .less than & cm0! superficial .not exten ing $eyon the superficial fascia0! an low gra e are groupe together as tumors with a fa#ora$le prognosis" Tumors that are large .more than & cm0! eep .exten ing $eyon the superficial fascia0! an high gra e ha#e a poorer prognosis" Tra itionally! soft tissue sarcomas ha#e $een treate surgically .4ig" 9*9?0" 3xperience has shown that excision of only the tumor results in a local recurrence rate of 90 percent $ecause of the Fpseu ocapsule!G an outer sheath of #ia$le tumor cells that is strippe away an left $ehin after simple excision" )ocal recurrence rates are aroun ;0 percent after more extensi#e resection an /0 to 9& percent after ra ical muscle group soft* part resection or amputation" In a prospecti#e ran omi'e trial comparing amputation with wi e local excision plus ra iotherapy! local recurrences occurre in none of /@ patients treate with amputation! an ; of 9@ un ergoing com$ine treatment" 3il$er an associates reporte a : percent local recurrence rate for extremity sarcomas treate with preoperati#e chemotherapy an ra iotherapy! followe $y en $loc resection of primary tumor with lim$ sal#age" 2o ifications of the protocol .e"g"! re uction of ra iation ose to a total of 9?00E:000 c=y0 are associate with excellent tumor control an re uce woun toxicity" A 5uncti#e ra iation therapy! with or without chemotherapy! ecreases local recurrence after a conser#ati#e surgical approach that completely remo#es the tumor with a e(uate surgical margins" The surgeon an ra iation therapist i eally shoul plan their approach together" All areas of the operati#e site shoul $e irra iate to minimi'e local recurrence" RADIATION T13RA<> The effecti#eness of ra iation therapy! li+e surgical therapy! must $e assesse $y comparing local an regional tumor control with treatment* in uce mor$i ity" Ioni'ing ra iation is effecti#e in the management of a wi e #ariety of malignant tumors an is part of the treatment for &0 to @0 percent of patients with cancer" The ra iation oncologist shoul $e in#ol#e in the selection of patients an their e#aluation $efore! uring! an after treatment" Aith ra iation! tumors can $e estroye while anatomy is preser#e " Often function an cosmesis can $e preser#e if the anatomy is intact $efore treatment" Concurrent me ical pro$lems ha#e less influence on ra iation therapy than on surgical or chemotherapy! although treatment*relate se(uelae may $e more fre(uent or more se#ere in patients with certain systemic illnesses! such as ia$etes or collagen #ascular isease"

The ifferential effect of ra iation on tumors an normal tissues results in a fa#ora$le therapeutic ratio in most clinical situations" Ra iation can! howe#er! ha#e imme iate an elaye si e effects on normal tissues" The inci ence an se#erity of late se(uelae! which may progress o#er many years! are highly epen ent on treatment techni(ue" The type of e(uipment use ! fiel arrangement! accuracy of tumor locali'ation an fiel placement! treatment sche ule! an expertise of the treating physician all influence outcome" The appearance of late se(uelae may $e the unfortunate conse(uence of treatment techni(ues long a$an one " <hysical Dasis Ioni'ing ra iations are characteri'e $y their capacity to ioni'e .an excite0 atoms an molecules in an a$sor$er such as tissue" 3lectromagnetic ra iations can $e pro uce artificially in +ilo#oltage ra iation therapy units an linear accelerators $y impinging energetic electrons on a target .e"g"! tungsten0" The energy of the resulting x*rays is relate to the energy of the accelerate electrons as they reach the target material" 3lectromagnetic ra iations of characteristic energy .gamma rays0 are also pro uce $y the ra ioacti#e ecay of naturally occurring ra ioisotopes .e"g"! ra ium 99@0 or artificially pro uce isotopes .e"g"! co$alt @00" Accor ing to (uantum physics! x*rays an gamma rays can also $e represente as particles calle photons" Remo#al of the target in a linear accelerator results in an emitte $eam of high*energy electrons that ha#e ifferent a$sorption characteristics from photons an are #ery useful in the treatment of relati#ely superficial malignancies" Other types of particulate ra iations .e"g"! protons! neutrons! pi mesons! an helium ions0 are pro uce $y #ery powerful linear accelerators! or cyclotrons! an ha#e $een use therapeutically! primarily in in#estigati#e settings" Decause the $asic physical mechanisms of action of all ioni'ing ra iations are the same! the ifferent effects o$ser#e with e(ual physical oses result from ifferences in spatial or temporal istri$utions" 4or eca es! oses at the point of interest! such as the tumor or spinal cor ! were grossly extrapolate from s+in reactions or oses measure in air .in roentgens0" To ay clinical specification of ra iation oses is eri#e from irect measurements of a$sor$e oses within the patient .using thermoluminescent osimeters0 or from oses calculate within a tissue phantom that simulates the human $eing" <hantom measurements are a apte for precise clinical application through the use of computer programs" Recent technological a #ances ha#e ma e it possi$le to correct for tissue inhomogeneities .air ca#ities an $one0 within the treatment #olume using CT*$ase treatment planning" Until /9?0! a$sor$e ra iation oses were (uantifie in ra s! with / ra e(ual to 0"0/ 5oule per +ilogram of the a$sor$er" Accor ing to the /9?0 recommen ations of the International Commission on Ra iological Units! oses shoul $e (uantifie in gray .=y0 units! with / =y Q /00 ra Q / 5oule per +ilogram of the a$sor$er! an / c=y Q / ra " The a#aila$ility of mo ern ra iation therapy was initially facilitate $y wi esprea istri$ution of co$alt @0 teletherapy units! ating to /9;9! an the later #ersatile ; to @ 2eC linear accelerators" )inear accelerators that pro uce a range of photon an electron energies $etween ; an 9& 2eC are a#aila$le an are useful in a wi e #ariety of clinical situations" 2o ern e(uipment pro#i es eeply penetrating $eams! short treatment times! isocentric patient setups! impro#e s+in sparing! ecrease $one

a$sorption .compare with +ilo#oltage units0! an sharp $eam margins with less si e scatter than the co$alt @0 units" In some clinical situations! $rachytherapy! or the irect placement of ra ioacti#e sources within tissue! may permit eli#ery of tumor oses higher than those achie#a$le with external $eam ra iation therapy" Decause the ose eli#ere falls off in a manner proportional to the s(uare of the istance from the source! #ery high oses can $e eli#ere to tissues imme iately a 5acent to the implant with relati#e sparing of surroun ing normal tissues" A #ariety of artificially pro uce ra ioisotopes! inclu ing iri ium /99! cesium /:%! an io ine /9&! are use in the treatment of cancers of the $reast! prostate! $rain! lung! hea an nec+! gynecologic organs! soft tissues! an eye" 1igh* ose*rate .1DR0 remote afterloa e $rachytherapy! a new eli#ery techni(ue that is gaining greater clinical acceptance! in#ol#es the eli#ery of se#eral grays in minutes" )ow* ose* rate .)DR0 $rachytherapy may re(uire se#eral ays of hospitali'ation! $ut 1DR can $e eli#ere in a fractionate manner as an outpatient proce ure" In 1DR remote afterloa ing! a high*acti#ity source is ri#en to a pre etermine series of positions for specific perio s" Decause of the small source si'e! smaller* iameter catheters can $e applie to interstitial an intraluminal sites! such as the $ronchus! esophagus! an $ile uct! which pre#iously coul not $e easily treate with )DR techni(ues" This computer* operate remote afterloa ing techni(ue optimi'es the ose istri$ution" These $rachytherapy techni(ues ha#e le the ra iation oncologist into the operating room an into closer cooperation with the surgeon" Diologic Dasis Ra iosensiti#ity is the suscepti$ility of cells to in5ury $y ioni'ing ra iation" This in5ury may cause repro ucti#e cell eath $y interrupting the cell-s capacity to replicate in efinitely" Ra iation can +ill cells $y interfering with critical cell functions unassociate with cell replication .Finterphase eathG07 this is an important mechanism of ra iation*in uce cell eath in lymphocytes an in normal sali#ary glan " The inherent ra iosensiti#ity of most normal an transforme mammalian cells is remar+a$ly similar! with oses of //0 to 9;0 c=y consistently re ucing repro ucti#e cell sur#i#al to :% percent .D0 ose0" Therefore! ifferences in the rapi ity an completeness of response of human tumors an normal tissues must $e $ase on other factors! such as the capacity to repair su$lethal amage! tissue oxygenation! cell cycle time an istri$ution! an repopulation" Ra iocura$ility is the a$ility of ra iation to control a tumor permanently! allowing sur#i#al of the host" Tumor type! si'e! site! an extent ha#e a greater influence on ra iocura$ility than cellular ra iosensiti#ity" Ra ioresponsi#eness! or the rapi ity of a tumor-s response to ra iation! may not correlate well with ra iocura$ility" 3pi ermoi carcinomas of the oral ca#ity! larynx! s+in! an cer#ix an a enocarcinomas of the $reast! cer#ix! an prostate may $e ra iocura$le espite relati#ely slow responses to ra iation! an un ifferentiate carcinomas often respon rapi ly to ra iation treatment $ut usually are not cure $ecause of wi esprea tumor issemination" 1owe#er! ifferences in ra ioresponsi#eness of tumors of a specific type an site may correlate with local tumor control" Normal tissues ha#e a greater capacity to repair in5ury than o tumor cells" 4ractionation! or the i#ision of a ra iation ose into multiple smaller oses! allows

reco#ery of this amage $etween ra iation fractions" )a$oratory an clinical stu ies in icate that an interfraction inter#al of at least ; to @ hours is necessary to permit maximal repair of su$lethal in5ury" Decause of their greater repair capacity! slowly i#i ing normal tissues usually are spare more than tumor cells $y the use of relati#ely small fraction si'es! $ut rapi ly i#i ing stem cell populations! such as $one marrow an mucosal surfaces! ha#e less capacity for repair" The use of small oses per fraction impro#es the therapeutic ratio $y re ucing the late normal tissue effects of ra iation more than the tumor effects" Although some protraction of treatment is necessary to permit repopulation of acutely respon ing normal stem cell populations an a#oi intolera$le acute normal tissue effects! treatment protraction also permits repopulation of tumor cells an shoul not $e excessi#e" 3mpirical e#i ence suggests that aily fractions of approximately 9 =y optimi'e the $alance $etween these effects" Clinicians ha#e $een in#estigating the use of altere ! hyperfractionate sche ules that use two or three small fractions per ay in an effort to further ecrease late normal tissue complications without increasing the o#erall uration of treatment" 4or similar reasons! cell +illing can $e mo ifie $y changes of the ose rate" To achie#e tolera$le in i#i ual treatment urations! external $eam ra iation therapy usually is eli#ere at a ose rate of 9 to & =yNmin" As the ose rate ecreases! cell +illing per unit of ose ecreases" )ow ose rates .i"e"! less than /0 c=yNmin0 may fa#or repair in normal tissues" This effect is exploite clinically to impro#e normal tissue tolerance .particularly of the lung0 in total*$o y irra iation an to allow eli#ery of #ery large total oses with low* ose*rate interstitial an intraca#itary $rachytherapy techni(ues" Ra iation*in uce cell +illing can $e mo ifie in other ways" Decause molecular oxygen must $e present for maximal cell +illing $y ioni'ing ra iation! tumor cellular hypoxia can ecrease the effecti#eness of ra iation therapy $y as much as a factor of :" This Foxygen effectG may explain the postirra iation persistence of tumor cells when there is necrosis or fi$rosis" The intrinsic ra iosensiti#ity of cells can $e increase $y altering the target DNA! such as $y replacing thymi ine with halogenate pyrimi ine analogues .DU R! IU R0 uring cell replication" Cell +illing can $e increase $y inhi$iting postirra iation repair processes" 4or example! the repair of DNA stran $rea+s can $e inhi$ite $y actinomycin D an oxoru$icin an $y heat .;9 to ;&C0" Unfortunately! current metho s of altering the target DNA an inhi$iting postirra iation repair are not selecti#e for tumor cells an may not impro#e the therapeutic ratio" Clinical Dasis Ta$le 9*9: is a partial list of tumors that are treate with ra iation" Irra iation may $e the only anticipate treatment or may $e com$ine with surgery an Nor chemotherapy" The intent of treatment may $e curati#e or palliati#e" In some clinical situations! surgery an ra iation pro#i e compara$le rates of local tumor control with (ualitati#ely ifferent si e effects" In these cases! the choice of treatment only can $e ma e $y a patient who has $een carefully informe $y a surgeon an ra iation oncologist" Ahene#er curati#e treatment of malignancy is $eing consi ere ! it is important that all the specialists .me ical! surgical! an ra iation oncologists0 are in#ol#e $efore initiation of therapy" <re#ious surgical an chemotherapeutic management can significantly influence the therapeutic ratio of su$se(uent ra iation

therapy" Close cooperation from the $eginning of therapy can often impro#e treatment outcome significantly" 4or example! careful mar+ing of the margins of a tumor uring surgery can help the ra iation oncologist efine a more accurate target #olume an ecrease the mor$i ity of therapy" Aw+war placement of a surgical incision can ramatically increase the #olume! complexity! an mor$i ity of su$se(uent irra iation" In some cases! the ra iation oncologist can o$tain #alua$le information $y o$ser#ing the operati#e fiel " Decisions a$out the utility of ra iation therapy are $ase on tumor*relate factors .type! site! extent! typical natural history0 an host factors .general con ition! status of local an regional tissues0" In almost all cases! efiniti#e tissue iagnosis shoul $e o$taine $efore treatment to a#oi inappropriately mor$i treatment of $enign con itions that mimic malignancy" On rare occasions when $iopsy poses an unreasona$le ris+ to the patient .e"g"! tumors of the $rainstem an optic tract0! treatment may $e initiate on the $asis of strong ra iologic iagnostic e#i ence" The intro uction of CT an 2RI shoul re uce iagnostic errors in these situations" 1istologic tumor type an gra e may $e useful pretherapeutic pre ictors of $iologic $eha#ior an ra iocura$ility" The potential for local an regional tumor control is closely relate to tumor si'e an the primary site" In most cases! ra iation ose is limite $y the tolerance of surroun ing normal tissues" The pro$a$ility of controlling a tumor with a tolera$le ose of ra iation is in#ersely proportional to its si'e an the num$er of proliferating clonogens that must $e eliminate " 6urgical tumor e$ul+ing proce ures that lea#e gross resi ual isease are sometimes necessary to relie#e tumor* relate symptoms7 they usually re uce the num$er of clonogens $y less than one log! may increase tumor hypoxia! may ecrease the tolerance of a 5acent normal tissues! an rarely impro#e ra iocura$ility" )arge tumors are more li+ely to ha#e sprea regionally! sometimes re(uiring treatment of a larger #olume with a conse(uent re uction of normal tissue tolerance" The primary tumor site pre icts $iologic $eha#ior an ictates which normal tissues will $e affecte $y treatment" 4or example! small tumors of the glottic larynx rarely sprea to regional no es! an more than 90 percent of these tumors are cure with mo erate oses of ra iation to a small local fiel " Dy contrast! tumors of similar si'e originating a few millimeters away in the supraglottic larynx ha#e a richer lymphatic supply! are associate with a greater li+elihoo of regional sprea ! an often re(uire treatment with relati#ely large fiel s encompassing the regional lymph no es" 3#en fairly large tumors of the cer#ix can $e controlle locally with minimal ris+ of serious mor$i ity $ecause of the high ra iation tolerance of the uterus an #agina an the a$ility to eli#er high oses with intraca#itary therapy" Carcinomas of similar si'e in the upper a$ omen are rarely controlla$le with ra iation therapy alone $ecause surroun ing normal tissues such as li#er! +i ney! $owel! an spinal cor limit the eli#era$le oses of external $eam ra iotherapy" Intraoperati#e ra iotherapy .the eli#ery of external $eam ra iotherapy irectly to a tumor expose uring an operation0 is currently $eing in#estigate as a possi$le means of increasing the ra iation ose that can $e eli#ere in such situations" =oals If the cancer is cura$le! a prolonge treatment course an a mo erate ris+ of serious treatment*relate mor$i ity are often accepte in an effort to o#ercome life*

threatening isease" If the o$5ecti#e is palliation of cancer* relate symptoms! treatment must $e esigne to minimi'e mor$i ity an incon#enience an maximi'e symptom relief" 3#en when seemingly in icate ! ra iation therapy coul $e inappropriate $ecause of host factors" De$ilitate or isoriente patients may not tolerate aily treatment" )ocal tissue changes in uce $y comor$i isease may cause the ris+ of curati#e treatment to outweigh the chance of $enefit" Dosage an Deli#ery Treatment planning an eli#ery re(uire close cooperation among health professionals! inclu ing me ical physicists! osimetrists! ra iation therapy technologists! ra iation therapy nurses! an ra iation oncologists" The ra iation oncologist $egins $y efining a target #olume $ase on the patient-s me ical history! physical examination! ra iologic stu ies! operati#e escription! an pathology reports" This etermination also consi ers the natural history of the isease! its anatomic routes of sprea ! an possi$le interactions among ra iation! surgery! chemotherapy! an intercurrent isease" The therapeutic approach is esigne to maximi'e the chance of tumor control an minimi'e the ris+ of treatment*relate mor$i ity" In most cases! the primary tumor an a 5acent area at ris+ for regional sprea are graphically isplaye an incorporate in a planne target #olume" Ra iation can $e eli#ere $y multiple $eams of photons or electrons! sometimes augmente $y interstitial or intraca#itary applications" Deam* shaping e#ices may $e use to alter epth ose istri$utions an to shape the ra iation fiel " The osimetry ata are incorporate in computer* assiste programs that allow rapi ! accurate calculations of the esire options" The chosen treatment fiel s are simulate on the patient using a speciali'e machine $uilt to the geometric specifications of the treatment machine $ut fitte with a iagnostic x*ray hea an fluoroscope" The patient can $e fitte with immo$ili'ation e#ices to impro#e the repro uci$ility of treatment" 2ar+s on the patient-s s+in ma+e it possi$le to repro uce the simulate fiel s uring treatment" Aith careful immo$ili'ation an fiel locali'ation! repetiti#e treatment eli#ery can $e accurate to within a few millimeters" Different sites in the same patient can $e treate with ifferent oses accor ing to ris+ an the amount of tumor in#ol#ement" A relati#ely large #olume inclu ing the primary tumor an surroun ing areas at ris+ for har$oring microscopic isease may $e treate using a mo erate ose" The primary tumor! grossly in#ol#e lymph no es! or positi#e surgical margins may then $e F$ooste G to a higher ose with smaller external $eam fiel s or with $rachytherapy" Ahen the goal of treatment is palliation! the treatment ose an sche ule are chosen to achie#e symptom relief as (uic+ly as possi$le! with little or no treatment*relate mor$i ity" Decause the ose is usually not pushe to normal tissue tolerance an the patient is not expecte to sur#i#e to experience late effects of ra iation! relati#ely large aily fractions may $e use to shorten the o#erall treatment time" Treatment is gi#en only to relie#e symptoms or occasionally to pre#ent imminent pro$lems .e"g"! to pre#ent fracture in tumorous weight*$earing $ones0" Occasionally! aggressi#e ra iotherapeutic treatment of hematogenous metastases may $e in icate ! particularly if the lesion is solitary an presents after a long isease*free inter#al" Com$ination 2o alities

Ra iation therapy alone is curati#e in many clinical situations" Aggressi#e local or locoregional treatment yiel s high cure rates in many types of hea an nec+ cancer! gynecologic malignancies! anal cancer! prostate cancer! 1o g+in-s isease! an other neoplasms" In other cases! ra iation is use in com$ination with surgery or chemotherapy" Ra iation an surgery may $e irecte to the same site! e"g"! when resection of a cancer of the hypopharynx is followe $y irra iation! or when irra iation of a soft tissue sarcoma in an extremity is followe $y surgery" Com$ine mo alities may ecrease the mor$i ity associate with either mo ality alone" )ocal tumor excision plus ra iation therapy is an alternati#e to mastectomy for $reast cancer" Treatment of soft tissue sarcomas with wi e local excision an preoperati#e or postoperati#e irra iation achie#es local control rates compara$le to amputation $ut with preser#ation of the lim$" In some cases! ra iation an surgical treatment are irecte to ifferent sites! e"g"! when orchiectomy is followe $y irra iation of the retroperitoneal lymph no es! or when a nec+ issection follows interstitial irra iation of a cancer of the oral tongue" <ostoperati#e ra iation impro#es local an regional control rates in many postsurgical situations" Decause patients selecte for postoperati#e therapy ten to $e those with unfa#ora$le clinical or histologic features! retrospecti#e stu ies usually o not compare similar groups of patients an o not answer important (uestions a$out the influence of postoperati#e treatment on sur#i#al" 1owe#er! e#en when the sur#i#al $enefit of postoperati#e ra iation is uncertain! treatment may $e in icate to pre#ent local recurrence" Ahen surgery an ra iation therapy are irecte to the same site! the inter#al $etween them epen s on a range of factors" 2o erate* ose irra iation of a soft tissue sarcoma may $e followe $y resection in /0 to /; ays7 rectosigmoi resection shoul $e elaye ; to @ wee+s after pel#ic irra iation to allow for regression of e ema an hyperemia" 2ost postoperati#e ra iation therapy is eli#ere with relati#ely high oses irecte to sites at high ris+ for persistent tumor" The optimal timing of postoperati#e ra iotherapy epen s on the type of surgical proce ure! patient reco#ery! woun healing! an tumor characteristics an shoul $e eci e $y the surgeon an ra iotherapist" Unnecessary elays may allow time for tumor regrowth an ecrease the efficacy of ra iotherapy" <lanne com$ine treatment shoul not $e confuse with the use of one metho after failure of another approach that often re uces the effecti#eness of the secon metho " 4or example! irra iation of a tumor regrowing in tissues altere $y surgery is li+ely to $e ineffecti#e $ecause of ecrease #ascularity an increase tumor #olume" It may ha#e a higher mor$i ity $ecause of a$ ominal a hesions that fix segments of $owel within the high* ose #olume" Con#ersely! an aggressi#e course of ra iation therapy that lea s to fi$rosis! loss of tissue planes! an ecrease #ascularity increases the inci ence of complications from su$se(uent ma5or surgery" 6i e 3ffects Any effecti#e anticancer therapy can pro uce un esira$le an occasionally angerous si e effects" Acute ra iation*in uce si e effects can $e istressing $ut can usually $e manage conser#ati#ely an are almost always self*limite " The nature of these effects! summari'e in Ta$le 9*9;! epen s on the tissues inclu e within the target #olume"

The clinically important late se(uelae of ra iation therapy may not $e apparent until months or e#en years after completion of treatment" The ris+ of late complications can usually $e minimi'e .$ut not eliminate 0 $y careful techni(ue" In many situations! an effort to eliminate a small*to* mo erate ris+ of ma5or complications $y re ucing the ra iotherapy ose will increase the ris+ of tumor recurrence" The ris+ of secon malignancies in uce $y ioni'ing ra iation is small" In stu ies of more than 9!000 patients with hea an nec+ cancer an 9!000 patients with cancer of the $reast! no increase in the inci ence of secon cancers coul $e emonstrate in patients treate with ra iotherapy" The increase inci ence of leu+emia in patients treate for 1o g+in-s isease was strongly correlate with exposure to al+ylating agents! although many of the patients also recei#e ra iation therapy" A #ery slight increase in the inci ence of myelogenous leu+emias .o$ser#e 8expecte Q /";0 was note in 99!;9: patients o$ser#e for @0!000 person*years after ra iation for cer#ical carcinoma" 2ANA=323NT O4 CANC3R AT DI6TANT 6IT36 Clinical 3#aluation an 6creening If an initial screening appraisal in icates the nee for a more extensi#e metastatic sur#ey! then the presence an extent of metastases shoul $e assesse $y a comprehensi#e $ut cost*effecti#e iagnostic e#aluation" Components of this e#aluation epen on the signs an symptoms of isease in a particular area .Ta$le 9* 9&0 an the goals of treatment .cure #ersus palliation0" )a$oratory tests! except for screening! shoul not $e or ere unless the results woul change the treatment plan" Other factors to $e consi ere are the cost an a#aila$ility of further tests! prognostic factors! an the natural history of the isease" These principles are also important postoperati#ely in etermining how long an how often to follow the patient an what types of screening tests shoul $e use " In general! the patient shoul $e e#aluate e#ery : to ; months for the first 9 years! at @* month inter#als to the fifth year! an then at least once a year in efinitely" Chest x* rays an Nor la$oratory tests are o$taine initially at @*month inter#als an then yearly or as in icate " The exact fre(uency of screening epen s on the ris+ of recurrent metastatic isease7 patients with #ery early cancer .e"g"! melanomas less than /"0 mm0 might $e e#aluate at @*month to /9*month inter#als from the $eginning! $ut those at high ris+ for metastases shoul $e e#aluate e#ery 9 to : months uring the first 9 years" Decause a large proportion of recurrences are etecte $y the patients themsel#es! high*ris+ patients shoul $e $riefe on possi$le symptoms an urge to see+ imme iate me ical attention shoul they appear" 1istory an <hysical 3xamination A hallmar+ of metastatic isease is a symptom complex that progresses in intensity or fre(uency" A careful history an physical examination are the most sensiti#e! specific! an cost*effecti#e means of e#aluating possi$le metastatic isease! short of a $iopsy" )a$oratory an Ra iological Tests The chest x*ray shoul $e use routinely for screening" Ahole*lung tomograms or CT scans of the chest are useful for e#aluating suspecte pulmonary! pleural! or me iastinal metastases .4ig" 9*990" 6erum li#er function tests! inclu ing lactic

ehy rogenase le#el! are important screening tools for metastatic isease" An isolate ele#ation of the serum al+aline phosphatase or lactic ehy rogenase le#el is presumpti#e e#i ence of metastatic isease" A CT or ultrasoun scan of the a$ omen shoul $e o$taine if physical examination or a$normal li#er chemistry suggests intraa$ ominal metastases" 6ome soli tumors pro uce circulating tumor secretory pro ucts that represent mar+er molecules" These tumor mar+ers can $e use to monitor for recurrence or assess the response to treatment .see Ta$le 9*900" 2ar+er molecules are not infalli$le! howe#er! an a tumor cell population may emerge that fails to secrete the mar+er $eing monitore " Done an $rain scans are not in icate for routine screening of occult metastatic isease $ecause their iagnostic yiel is low! except for those cancers that fre(uently relapse first in the $one! such as $reast cancer an prostate cancer" A ra ionucli e $one scan is the most sensiti#e test for s+eletal metastatic isease! $ut a careful history an irecte ra iographs are necessary to ensure that areas of upta+e o not represent areas of ol trauma or inflammation" <ositron emission tomography .<3T0 has $ecome a wi ely use in#estigati#e an clinical tool for cancer etection an iagnosis! cancer staging! an cancer treatment monitoring" This use of <3T technology is $ase on the o$ser#ation that malignant transformation of cells is associate with an increase glycolytic rate .e#en in the presence of oxygen0! which is correlate with upta+e of fluorine*/? eoxyglucose .4D=0" <3T scanning can etect tumors as small as /0 mm" It is useful for etecting $rain tumors! metastatic melanoma! an metastatic malignancies of the hea an nec+! $reast! lung! an colon" <athologic Tests The efiniti#e iagnosis of metastatic isease is ma e $y $iopsy analysis" An excisional or nee le $iopsy proce ure is relati#ely easy when the suspecte metastasis is superficial" Deeper lesions may also $e approache with a fine*nee le $iopsy" In many circumstances! a clinical iagnosis ma e $y ra iologic stu ies is sufficient! especially if metastases in#ol#e more than one site at the same time an the a$normality was a$sent on pre#ious stu ies" Cytologic examination of urine! sputum! cere$rospinal! peritoneal! or pleural flui ! or of $one marrow also may yiel a iagnosis of metastatic isease! especially with specific symptoms refera$le to these areas" A common pro$lem in the iagnosis of metastatic cancer is istinguishing a metastatic lesion from a primary anaplastic! un ifferentiate carcinoma or lymphoma! e"g"! when an anaplastic lung lesion appears in a patient who ha a primary anaplastic or un ifferentiate carcinoma or lymphoma" Ahen an anaplastic lung lesion appears in a patient who ha a primary melanoma remo#e & years pre#iously an is a hea#y cigarette smo+er! shoul this $e iagnose as a metastatic melanoma or a lung carcinomaR 3lectron microscopy an immunostaining with anti$o ies of cytologic specimens an tissue specimens can $e crucial in ai ing the pathologist in the iagnosis" =eneral <rinciples of Treatment

The treatment of a patient with a #ance cancer epen s on the num$er an sites of metastases! their rate of growth! types of! an responses to! pre#ious treatment! an the patient-s age! o#erall con ition! an esires" 4or example! #igorous treatment might $e appropriate for a slowly growing solitary metastasis! $ut only symptomatic treatment! or none at all! might $e use in a e$ilitate patient with multiple metastases for whom prior treatment has faile " The option of no treatment is particularly important in patients who are asymptomatic! terminally ill! or #ery ol " 4or example! a physician may choose to o$ser#e an asymptomatic patient with slowly growing tumors in sites such as the lung" Suality of life is maintaine in this instance! an treatment can $e institute when the si'e or num$er of metastases increases or when the patient e#elops symptoms" A patient shoul ne#er $e enie treatment when there is a reasona$le expectation of success an an accepta$le ris+ of toxic effects" The num$er of organs or tissues containing metastases is the most significant factor pre icting sur#i#al in patients with istant metastases" 4or example! the me ian sur#i#al is % months for melanoma patients with metastasis to one site! ; months for those with metastases to two sites! an only 9 months for those with metastatic isease at three or more sites" The location of the metastases is also important" 6ites associate with relati#ely fa#ora$le outcomes for melanoma an $reast cancer inclu e .in approximately escen ing or er of fre(uency0 the s+in! su$cutaneous tissue! istant lymph no es! $one! an lung" Unfa#ora$le outcomes are associate with metastases to the li#er an $rain" 2etastases in fa#ora$le sites are associate with long*term sur#i#al .i"e"! 9 to & years0 in a small $ut measura$le proportion of patients" If the patient has recei#e pre#ious therapy! such as chemotherapy or surgery for a systemic metastasis! the sur#i#al time is li+ely to $e shorter" <atients in a e$ilitate state are less li+ely to withstan #igorous treatments than those who are not suffering symptoms of metastatic isease" Defining the =oals! Denefits! an Ris+s of Treatment The first goal of treatment is relief of symptoms" Treatment to relie#e symptoms is worthwhile! especially when the $enefit of symptom relief excee s the ris+ of toxic effects an mor$i ity" Its efficacy can $e monitore $y su$5ecti#e an o$5ecti#e assessment of the symptoms cause $y the metastases" The secon goal of treatment is to prolong life" This has not $een achie#e in most patients with a #ance cancer" One exception is the surgical remo#al of solitary metastases from s+in an su$cutaneous tissues or #isceral sites such as the lung or $rain .see 4ig" 9*9%0" Curati#e surgical excision of solitary metastases of melanoma in #isceral organs can lea to &*year sur#i#al rates excee ing ;0 percent" Ta$le 9*9@ presents the treatment mo alities for patients with metastatic isease" The choice of treatment shoul consi er potential toxicity! re(uirements for hospitali'ation! fre(uency of treatments! an me ian time necessary to attain antitumor response" The physician must un erstan the potential ris+s of each treatment as they apply to a particular patient" <atients who ha#e a goo performance status .who are a$le to care for themsel#es an ha#e no e$ilitating symptoms from their isease0! goo car iac an pulmonary function! an a e(uate white $loo cell an platelet counts are usually can i ates for clinical trials" A#aila$le effecti#e metho s for relief of symptomatic isease shoul $e consi ere first"

<atient Counseling One of the greatest causes of anxiety for the cancer patient is uncertainty" <atients shoul $e counsele so that they can participate in treatment ecisions! cope with their isease realistically! an arrange their personal li#es" Although some patients o not want a full presentation of the facts! some iscussion is warrante $ecause it is ifficult to initiate treatment without explanation" If the physician an the patient o not communicate honestly an openly! the patient coul lose trust in the physician an might not accept su$se(uent treatment recommen ations" Ahen counseling patients an their families! the physician must $e sympathetic! realistic! an hopeful a$out the results of treatment" <atients nee hope! an e#en in grim situations treatment can achie#e certain goals! if only the relief of symptoms" In other wor s! the physician shoul continue treating the patient e#en when it is no longer possi$le to treat the cancer" The approach epen s on the patient-s prognosis! physical con ition! an emotional sta$ility" The patient-s esires shoul $e strongly consi ere when choosing among alternati#e forms of palliati#e treatment" 6urgery Curati#e <roce ures Once a neoplasm has metastasi'e to a istant site! it shoul no longer $e cura$le $y surgical resection! $ut remo#al of metastatic lesions in the lung! li#er! or $rain has occasionally pro uce a clinical cure .4ig" 9*:00" Therefore! in selecte patients with slowly growing neoplasms! curati#e resection of the metastatic lesions may $e in icate ! especially if the metastasis is solitary" O$ser#ation for se#eral wee+s or months sometimes pro#i es rele#ant information a$out the rate of tumor growth an the possi$ility of metastases emerging at other sites" All patients consi ere for curati#e resection must un ergo an extensi#e wor+up to rule out metastatic sprea " Among the components of this wor+up are a complete $loo count an serum chemistry panel! applica$le serum tumor mar+ers! 2RI of hea ! CT of chest! a$ omen! an pel#is! an a $one scan! if applica$le" Newer whole*$o y imaging stu ies! such as <3T scanning! may e#entually replace con#entional ra iologic techni(ues" Curati#e resection shoul $e attempte only if the lesions are accessi$le an the proce ure can $e performe safely" <alliati#e <roce ures 6urgical proce ures are sometimes in icate to relie#e the symptoms or re uce the se#erity of isease! or to prolong a useful! comforta$le life without attempting cure" A palliati#e operation that impro#es (uality of life $y relie#ing pain! hemorrhage! o$struction! or infection is 5ustifie when it can $e one safely without great iscomfort to the patient" 6urgery that only prolongs a misera$le existence oes not $enefit the patient" 6ome examples of palliati#e surgical proce ures are colostomy! enteroenterostomy! or gastro5e5unostomy to relie#e o$struction7 chor otomy to control pain7 cystectomy for infecte ! $lee ing tumors of the $la er7 amputation for painful infecte tumors in the extremities7 simple mastectomy for carcinoma of the $reast! e#en in the presence of istant metastases! when the primary tumor is infecte ! large! ulcerate ! an locally resecta$le7 colon resection in the presence of hepatic metastases7 an $iliary $ypass proce ures" A itionally! gastrostomy or 5e5unostomy may $e un erta+en to impro#e nutritional inta+e an a ministration of me ications" Cere$ral metastases that are not resecta$le $y con#entional surgical techni(ues can $e

a$late $y stereotactic ra iosurgery using a Fgamma +nifeG that eli#ers focuse ra iation to specific $rain lesions" The ecision to use palliati#e surgery epen s on the site of the isease an the uration of anticipate sur#i#al" If the patient-s life is measure in wee+s! the surgical a$lation of a metastasis is not 5ustifie ! $ut longer anticipate sur#i#al may ren er excision of gross isease worthwhile" Ra iation Therapy Irra iation has a role in the treatment of patients with a #ance cancer! particularly those with symptomatic lesions" It is use as palliati#e treatment for patients with $one or $rain metastases an for symptomatic lesions locate in the s+in! su$cutaneous tissues! or lymph no es" Ra iation therapy using high*energy $eams relie#es the pain of $one metastases! often within / wee+" Cranial .whole*$rain0 an spinal cor irra iation is use for central ner#ous system metastases" Irra iation from high*energy proton $eams using a linear accelerator also can effecti#ely treat superficially locate metastases in the s+in or soft tissues" Chemotherapy 2o ern use of chemotherapy $egan in the /9;0s with the a ministration of hormonal therapy using an rogens an estrogens an the use of the al+ylating agent nitrogen mustar " Throughout the /9&0s! chemotherapy was gi#en on empirical groun s! using oses an sche uling pre#iously foun to $e successful in antimicro$ial therapy" Daily oral a ministration of fixe rugs was generally use " Although responses were occasionally seen! clinical relapse was uni#ersal" In the early /9@0s! 6+ipper foun e the principles still use in esigning chemotherapeutic trials8 ./0 A single cancer cell can grow into a lethal tumor mass" .90 The rate of tumor growth .tumor ou$ling time0 slows with increasing tumor $ur en in the later stages of tumor growth" .:0 2ost chemotherapeutic agents exhi$it log cell +ill +inetics! an the same increment of log cell +ill is seen with su$se(uent oses" .;0 Tumor $ur en is in#ersely relate to cura$ility $y chemotherapeutic agents" The comparison of antimicro$ial therapy for $acterial infections an chemotherapy for malignant isease has ma5or limitations" An immunocompetent host recogni'es $acterial antigens as foreign an mounts a efense" Antimicro$ial therapy will +ill $acteria or arrest $acterial proliferation until host anti$o ies an immune effector cells expan to eliminate remaining #ia$le $acteria" Dy contrast! a cancer patient-s immune system may not recogni'e tumor cells as foreign $ecause tumors arise from normal cells through mutational e#ents that uncommonly lea to significant cell* surface alterations" 3#en after significant cell +ill $y chemotherapy! the host-s immune system may not recogni'e an attac+ the remaining #ia$le tumor cells! allowing their regrowth .4ig" 9*:/0" 6ystemic or regional eli#ery of iffusi$le pharmacologic agents can estroy or arrest tumor cells capa$le of proliferation" Currently a#aila$le rugs are not selecti#e for

tumor cells7 they affect all i#i ing an some (uiescent cells" 6ince most agents act on one or more stages of cell cycle! cells an tissues with the highest growth fraction will $e most affecte " Chemotherapy attempts maximal tumor cell +ill with minimal an accepta$le toxicity to normal host tissues" The primary target of chemotherapeutic agents is the tumor stem cell" Complete estruction of all tumor stem cells is essential for cure" <ioneering stu ies with )/9/0 murine leu+emia! which has a /00 percent growth fraction! fostere the concept of log tumor +illing" If a single ose of rug re uces the tumor cell num$er $y 99 percent .a 9*log +ill0! then su$se(uent i entical rug oses will ecrease tumor cell num$er $y the same log ecrements" If a / cm tumor contains approximately /09cells! then e#en a 99"999 percent cell +ill .a &*log +ill0 will lea#e /0;#ia$le tumor cells" The so*calle clinical complete response! efine as isappearance of all measura$le isease! usually results in recurrent isease $ecause se#eral million #ia$le! $ut un etecta$le! proliferating cells may still $e present in one or more sites" Chemotherapy was initially attempte to cure patients with macrometastatic isease" Although chemotherapy is still important for gross metastatic isease an may pro uce ramatic clinical responses! cures are rare an limite to some pe iatric malignancies! hematologic malignancies! 1o g+in-s an some non*1o g+in-s lymphomas! testicular neoplasms! an choriocarcinoma" 3(ual attention is $eing irecte towar preoperati#e chemotherapy an postoperati#e treatment for presume micrometastatic isease" 2ost human tumors o not un ergo exponential growth in #i#o $ut emonstrate a slowing of growth with progressi#e tumor si'e" The growth fraction pea+s well $efore clinical etection" 6maller*#olume isease is presume to $e more responsi#e to rugs acti#e against proliferating cells an pro#i es the rationale for treatment in a postoperati#e or a 5u#ant setting" Resistance to Chemotherapeutic Agents The concept of tumor cell log +ill presumes that all cell su$populations within a tumor are chemosensiti#e" Clinical rug resistance is responsi$le for the ma5ority of chemotherapy failures" Resistant su$populations of cells may exist e no#o within tumors or may arise $y spontaneous or in uce mutations" Chemoresistant cells pro$a$ly o not emerge until a tumor reaches a critical mass of approximately /0!000 to /0 million cells" This may ta+e se#eral years for many soli tumors" A$o#e this mass! the li+elihoo of one or more chemoresistant clones increases exponentially with su$se(uent tumor growth" It is extremely important to $egin chemotherapy as early as possi$le" There appear to $e se#eral ifferent general mechanisms of rug resistance for ifferent classes of chemotherapeutic agents .Ta$le 9*9%0" Tumors are often resistant to se#eral agents that may $e structurally unrelate " This multi rug resistance .2DR0 can also occur $y se#eral ifferent mechanisms" An 2DR gene has $een i entifie 7 its protein pro uct! <*glycoprotein! causes the efflux of se#eral ifferent rugs from the intracellular space of target host cells in #itro" Drugs affecte $y o#erexpression of the 2DR gene inclu e se#eral natural pro ucts! such as the anthracycline oxoru$icin! the #inca al+aloi s #in$lastine an #incristine! actinomycin D! an the epi ophyllotoxins! such as etoposi e .C<*/@0" 1igh le#els of <*glycoprotein are foun in normal cells lining the luminal spaces of the gastrointestinal tract! li#er! an +i ney! where this gene pro uct is presume to in uce an acti#e efflux of

en#ironmental toxins from the $o y" The efflux pump can $e $loc+e in #itro $y calcium channel $loc+ers! such as #erapamil! which is currently un ergoing clinical stu y" Other compoun s that are effecti#e in re#ersing 2DR inclu e tamoxifen! cyclosporin A! a nonimmunosuppressi#e analog of cyclosporin .6DT <6C ?::0! an an antifungal tria'ole .itracona'ole0" The search for potent! selecti#e mo ulators of 2DR will promote a new generation of agents" Compoun s that are acti#e in #itro an in #i#o inclu e8 R6*::99&*/9?! 6R::&&%! a new (uinoline eri#ati#e .26*9090! a no#el tria'inoaminopiperi ine .69%??0! an an acri onecar$oxami e eri#ati#e .=4 /909/?0" Other mechanisms of 2DR inclu e8 alterations in rug*con5ugating en'ymes! such as glutathione 6* transferase7 alterations in components of the cytochrome <*;&0 en'yme complex! such as aryl hy rocar$on hy roxylase7 or alterations in rug transport en'ymes! such as glucuronyl transferase" A itionally! 2DR may in#ol#e allosteric alterations in DNA through interference with acti#ity of topoisomerase II! an en'yme responsi$le for maintaining DNA-s secon ary an tertiary structure" 2olecular pro$es are $eing e#elope to i entify a itional genes in#ol#e in 2DR" Anti$o ies against <* glycoprotein are a#aila$le an un er in#estigation for iagnostic an therapeutic use" A new mar+er for 2DR has $een escri$e " 6pecific glycosylate lipi s appear to $e expresse in high le#els in rug*resistant cells an tumors" Detection of these lipi s may signal the nee for aggressi#e chemotherapy in com$ination with the new 2DR mo ulators" Classification of Chemotherapeutic Agents Anticancer rugs may +ill tumor cells! $ut the ma5ority act $y pre#enting cell i#ision an cell proliferation" 2ost rugs affect one or more components of the cell cycle" The classification of anticancer rugs as non* cell cycle*specific! cell cycle*specific! or phase*specific is relati#e rather than a$solute" DNA synthesis can $e pre#ente $y $loc+ing the a#aila$ility of purine an pyrimi ine nucleoti e precursors" DNA may $e amage $y cross*lin+ing with unsta$le al+yl groups" DNA transcription can $e pre#ente $y irect $in ing of rug to DNA" 2itosis can $e arreste through $in ing of tu$ulin an pre#ention of mitotic spin le formation" Drug com$inations are often $ase on the complementary effects of phase*specific agents on rapi ly i#i ing cells! an non*cell cycle*specific agents on i#i ing an non i#i ing cells" Al+ylating Agents Al+ylating agents are non*cell cycle*specific agents that contri$ute an unsta$le al+yl group to cross*lin+ nucleic aci s .primarily DNA0" The ma5or effect is on cells in =/ or mitosis! $ut high oses may also ha#e cytotoxic effects on cells in =0" Al+ylating agents ha#e antitumor acti#ity against 1o g+in-s an non*1o g+in-s lymphoma! leu+emias! multiple myeloma! an carcinomas of the $reast! en ometrium! testis! an lung" Cyclophosphami e an cisplatin .CDD<0 are use in a #ariety of soli tumors" Dacar$a'ine .DTIC0 an ifosfami e ha#e ocumente antitumor acti#ity against soft tissue sarcomas an other neoplasms" Nitrosoureas are a su$group of al+ylating agents with increase lipi solu$ility! an $etter central ner#ous system penetration" They also may act $y car$amoylation! affecting DNA an RNA" They o not exhi$it cross* resistance with other al+ylating agents" There is a small $ut important inci ence of secon ary malignancies .especially leu+emias0 se#eral years after therapy with nitrosoureas"

Antimeta$olites These agents interfere with DNA an RNA synthesis an are phase*specific for the synthesis phase of the cell cycle" An exception is &*fluorouracil .&* 4U0! which is phase*specific an cell cycle*specific" Antimeta$olites are most acti#e in rapi ly proliferating tumors such as the hematologic malignancies $ut also ha#e wi e applica$ility in many soli tumors! especially $reast cancer an gastrointestinal malignancies" These rugs may inclu e structural analogues of meta$olites essential in normal growth an proliferation that $ecome incorporate as a false message! such as the pyrimi ine analogue cytara$ine .Ara*C0" Other actions inclu e re#ersi$le or irre#ersi$le $in ing to +ey or rate*limiting en'ymes in the synthesis pathways! such as the relati#ely irre#ersi$le $in ing of methotrexate to the en'yme ihy rofolate re uctase .D14R0" )euco#orin .folinic aci or citro#orum factor0 is the most sta$le form of folic aci an may $e gi#en to replenish the intracellular folate pool" It can $e a ministere after a high* osage methotrexate regimen to FrescueG normal tissues $y repleting folate an $ypassing the $loc+ at D14R" If gi#en in com$ination with &*4U! leuco#orin potentiates the antitumor effect of &*4U $y sta$ili'ing the co#alent $on of &*4 U2< .the acti#e meta$olite of &*4U0 to the en'yme thymi ylate synthase" <lant Al+aloi s Deri#ati#es of the periwin+le plant inclu e the #inca al+aloi s #in$lastine! #incristine! an #in esine" All three inhi$it mitosis $y $in ing microtu$ules an causing arrest in metaphase" The #inca al+aloi s ha#e antitumor acti#ity against 1o g+in-s an non* 1o g+in-s lymphomas! acute leu+emias! $reast! testicular! hea an nec+! renal! an cer#ical carcinomas! an other soli tumors" Although these three compoun s share a similar chemical structure! they ha#e a wi e spectrum of clinical acti#ity an toxicity" Deri#ati#es of the man ra+e plant! the epi ophyllotoxins etoposi e .C<*/@0 an teniposi e .C2*9@0! may act through inhi$ition of nucleosi e transport an incorporation into DNA an RNA" These rugs show phase*specific acti#ity for cells in =9 an late 6 phase" Clinical acti#ity has $een seen against lymphomas! leu+emias! lung! $la er! prostate! an testicular carcinomas! hepatomas! an other soli tumors" The plant al+aloi s are prominent targets for the <*glycoprotein pro uct of the 2DR gene! resulting in clinical rug resistance" Anti$iotics A wi e spectrum of antitumor rugs ha#e $een isolate from microorganisms" These rugs are generally consi ere non*cell cycle* specific agents an appear to interfere with the synthesis an Nor function of nucleic aci s" Doxoru$icin! $leomycin! mitomycin C! an actinomycin are examples that ha#e wi e clinical application" Doxoru$icin was eri#e from 6treptomyces species an has emonstrate acti#ity against many soli tumors! such as soft tissue sarcomas! carcinomas of the $reast! lung! esophagus! stomach! li#er! $la er! prostate! hea an nec+! testis! an en ometrium! among others" The mechanism of action appears to in#ol#e intercalation into DNA with triggering of topoisomerase II*me iate DNA clea#age to alter the tertiary structure of DNA" A close analogue! aunomycin! has shown antitumor acti#ity against acute lympho$lastic an myelo$lastic leu+emia"

Dleomycin was eri#e from a 6treptomyces species an causes single* an ou$le* stran $rea+s in DNA $ut not RNA" It has antitumor acti#ity against s(uamous cell carcinomas! lymphomas! testicular an lung carcinomas! malignant melanoma! soft tissue sarcomas! an mycosis fungoi es" 2itomycin C is a non*cell cycle*specific antitumor anti$iotic that acts as an al+ylating agent to cross*lin+ DNA an inhi$it DNA an RNA synthesis" Antitumor acti#ity has $een emonstrate against many gastrointestinal malignancies an $reast! lung! cer#ix! an $la er carcinomas" Dactinomycin .actinomycin D0 is an antitumor anti$iotic eri#e from a 6treptomyces species" It pre#ents DNA an RNA synthesis $y $in ing to the eoxyguanosine moieties of DNA" 6ingle*stran e DNA $rea+s ha#e also $een emonstrate " It has antitumor acti#ity against malignant melanoma! testicular tumors! choriocarcinoma! Ailms- tumor! neuro$lastoma! retino$lastoma! an se#eral sarcomas" 2iscellaneous Tamoxifen citrate is a nonsteroi al antiestrogen with cytostatic effects me iate through competiti#e inhi$ition of the estrogen receptor .3R0 an se#eral other emerging non*3R pathways" Tamoxifen has a clear role in the therapy of hormone* epen ent tumors of the $reast an prostate" Recent large stu ies ha#e emonstrate antitumor acti#ity against hormone receptor*negati#e $reast carcinoma an possi$le protection against contralateral an recurrent $reast carcinoma" A itionally! some $eneficial claims ha#e $een ma e regar ing the possi$le pre#ention of osteoporosis an atherosclerotic heart isease through an 3R effect" Although the 3R* me iate mechanisms of tamoxifen ha#e $ecome more complex an confusing! the clinical applications ha#e expan e as a result of the apparent $enefits an the relati#ely low toxicity of outpatient oral therapy" )e#amisole is an antihelmintic rug recently use as an antitumor agent $ecause of reporte immunorestorati#e acti#ity for functionally impaire macrophages an T lymphocytes" Two large! ran omi'e ! prospecti#e trials ha#e shown a sur#i#al $enefit in le#amisole com$ine with &*4U in the a 5u#ant treatment of mo ifie Du+e-s C a enocarcinoma of the colon" )e#amisole also is $eing use in com$ination with other agents for rectal carcinoma" Drug 6election The National Cancer Institute .NCI0 has esta$lishe three phases for testing new rugs prior to general a#aila$ility" <hase I clinical trials are esigne to etermine the maximal tolerate ose .2TD0 of rug! rug toxicity! an sche ule for use in phase II trials" <hase I trials usually are limite to patients whose a #ance isease has not respon e to stan ar treatments" 6chema fre(uently inclu e three patients at each escalating ose until toxicity is o$ser#e " <atients are informe that the li+elihoo for a ma5or clinical response is small! $ut responses are monitore an ocumente " <hase II clinical trials attempt to estimate the response rate of specific tumor types to a particular rug" 4ifteen to 9& patients with a specific tumor type are initially entere " If no responses are seen! the stu y is usually terminate " <hase II trials may or may not ran omi'e patients" <atients with a goo performance status an a minimum of pre#ious treatment are preferre ! to allow the highest pro$a$ility of showing a

fa#ora$le effect" Response to the rug must $e measura$le to allow (uantitati#e assessment" <hase II trials assess the acti#ity $ut not the efficacy of a particular rug" A minimal response rate of 90 percent is generally re(uire to procee to phase III trials" <hase III trials etermine whether a rug with +nown acti#ity contri$utes significantly to the treatment of a isease" A comparati#e stu y with new treatment #ersus stan ar treatment.s0 is use to etermine the efficacy of the new treatment" The stan ar treatment may consist of no treatment or other chemotherapeutic agents" )arge num$ers of patients! long follow*up! an extensi#e clinical an $iostatistical resources usually are re(uire " <atients in ifferent treatment groups must $e compara$le in e#ery way! inclu ing stratification for +nown or suspecte prognostic #aria$les! such as sex! age! an tumor stage" A ran omi'e ! controlle trial oes not use historical controls" It may ha#e se#eral treatment arms! $ut each patient is ran omly assigne to only one arm" As the num$er of treatment arms increases! so oes the num$er of patients re(uire for statistically #ali comparisons" <atient eligi$ility an entry! the timing an metho of ran omi'ation! an the en points to e#aluate response an toxicity are etermine $efore the start of the stu y" The en point of many phase III trials is o#erall sur#i#al! $ut other common stu y en points inclu e isease*free sur#i#al! tumor response rates! an palliation of symptoms" <hase III trials often re(uire multi*institutional participation to accrue sufficient num$ers of compara$le patients o#er a reasona$le perio " Intra* an interinstitutional (uality control is re(uire to reach #ali conclusions" Dose an Timing To achie#e maximal tumor cell +ill! the highest tolerate ose is gi#en o#er the shortest possi$le time" The osage is $ase on the 2TD eri#e from phase I an II stu ies an must $e tailore to a patient-s performance status! me ical illness! or organ ysfunction" Drug osing was tra itionally escri$e in milligrams per +ilogram .mgN+g0" The current! an more relia$le! stan ar of rug osing is in terms of $o y surface area! escri$e as milligrams per s(uare meter .mgNm90" There are many nomograms to con#ert mgN+g to mgNm9" A simple an relati#ely accurate con#ersion multiplies the mgN+g ose $y ;0 to yiel the mgNm9 ose" Alterations are often ma e for patients whose actual weight is mar+e ly ifferent from their i eal weight! e"g"! o$ese patients or patients with large #olumes of Fthir *space G flui collections! such as pleural effusions! ascites! or e ema" These alterations must consi er the rug-s pharmacology an #olume of istri$ution" The inter#al $etween oses epen s on a rug-s toxicity" 4or most chemotherapeutic agents with $one marrow toxicity! leu+openia an throm$ocytopenia $ecome e#i ent on a complete $loo count $y ay 9 or /0 an are most pronounce $etween ays /; an /?" Reco#ery usually $egins $y ay 9/ an is approximately 90 percent $y ay 9?" This pro#i es the rationale for a 9?* ay course or cycle of marrow*suppressi#e agents" Done marrow reco#ery time may $e elaye in onset or prolonge $ecause of pre#ious chemotherapy! ra iation therapy to marrow*pro ucing $one! or inherent toxicities of a few specific rugs! $ut an inter#al that is long enough to assure the safe reco#ery of $one marrow pro uction may also allow reco#ery an repopulation of

remaining tumor cells" A ministering com$inations of rugs can o#ercome the pro$lems of single* rug toxicity an rug*resistant cell populations" Com$ination Therapy an Dose Intensification 6ingle*agent therapy has pro uce cures only in choriocarcinoma an Dur+itt-s lymphoma" The $est strategy is to treat as small a tumor as possi$le! as early as possi$le! using a com$ination of rugs to minimi'e the emergence of resistant clones uring therapy" Com$ination chemotherapy is an attempt to pro#i e antitumor therapy to all resistant cell populations at the earliest possi$le time without increasing the toxicity to normal tissues" Com$ination therapy usually uses only those rugs that are also effecti#e as single agents against a particular tumor" Drugs with cell cycle an non*cell cycle specificity can $e com$ine to target $oth i#i ing an (uiescent tumor su$populations" Nono#erlapping toxicities are essential to a#oi life* threatening in5ury to normal tissues" Dose intensification has $een promote to allow comparisons of the relati#e effecti#eness of each rug use in com$ination therapy an to optimi'e rug ose eli#ery uring a course of com$ination chemotherapy" Relati#e ose intensity .RDI0 is the proportion of rug eli#ere per unit of time .usually / wee+0 relati#e to an ar$itrary stan ar ose of that rug o#er the same inter#al" 4or example! uring a 9?* ay cycle of com$ination therapy! a cyclophosphami e stan ar ose of ?0 mgNm9N ay $y continuous infusion .a ose intensity of &@0 mgNm9Nwee+0 is compare with a cyclophosphami e test regimen of /00 mgNm9N ay gi#en only on ays / to /; .a ose intensity of :&0 mgNm9Nwee+0" The RDI of the test regimen is :&0N&@0 Q 0"@:" The test ose of cyclophosphami e is higher uring the first half of the 9?* ay course! $ut the o#erall total ose per course is less than the stan ar ose" The importance of optimi'ing ose intensification has $een ocumente in la$oratory animal mo els $earing cura$le tumors! in which as little as a 90 percent ecrease in ose intensity of an effecti#e rug can result in a &0 percent ecrease in cure rate" Comparisons of ose intensity in com$ination rug trials for $reast! o#arian! an colon carcinomas an for lymphomas ha#e emonstrate a strong correlation $etween ose intensity an response rates" In uction! A 5u#ant! an Neoa 5u#ant Chemotherapy In uction chemotherapy is the use of chemotherapy as the sole form of treatment for a #ance isease" The patient usually has multiple sites of metastatic isease an is not a can i ate for locoregional treatment $y surgery or ra iation" If in uction chemotherapy is unsuccessful! a change to other chemotherapeutic agents or com$inations! or sal#age therapy! is consi ere " A 5u#ant chemotherapy is the use of regional or systemic chemotherapy after locoregional tumor elimination $y surgery or ra iation therapy" A 5u#ant therapy attempts to eliminate resi ual micrometastatic isease an usually is limite to patients at mo erate*to*high ris+ for local or istant recurrence" 6ince there is no tumor #isi$le at the time of treatment! response can $e e#aluate only $y monitoring rates of recurrence! isease* free sur#i#al! an o#erall sur#i#al" The choice of agents is $ase on response rates seen with a #ance isease of the same histologic type" Therapy is intensi#e $ut limite in uration7 any $enefit against microscopic isease is most li+ely to occur uring the first few courses! as long as a e(uate cytotoxic oses

are gi#en" 4ew stu ies show any a e $enefit to FmaintenanceG a 5u#ant chemotherapy" Neoa 5u#ant or primary chemotherapy is the use of chemotherapy as the first treatment for locali'e soli tumors such as $reast! gastrointestinal! an pe iatric carcinomas! extremity sarcomas! an locali'e lymphomas! among others .4ig" 9*:90" It has se#eral a #antages" 4irst! it may re uce the si'e of large or locally a #ance tumors! allowing a safer resection that spares surroun ing normal tissues! as in $reast conser#ation surgery! anal sphincter preser#ation with mi *to*low rectal tumors! an lim$ preser#ation with extremity sarcomas" 6econ ! tumor responsi#eness to chemotherapy can $e etermine while grossly or ra iologically #isi$le tumor is still present7 agents that pro uce an initial complete or ma5or partial response will $e continue postoperati#ely" A thir potential a #antage is imme iate treatment of possi$le micrometastatic isease" On the other han ! unsuccessful neoa 5u#ant chemotherapy can elay locoregional inter#entions! an tumor progression uring this time may preclu e safe resection or re(uire sacrifice of a itional normal surroun ing structures to o$tain a e(uate resection margins" <reoperati#e chemotherapy may confuse pathologic staging of resecte tissues! complicating future treatment ecisions an prognosis" Drug Deli#ery Intra#enous a ministration! the most common route for chemotherapeutic agents! eli#ers uniform oses of one or more rugs to all capillary $e s an en organs with +nown or presume metastatic isease" Regional arterial chemotherapy an intraperitoneal chemotherapy are other common routes of eli#ery" )ess common applications inclu e intra#esical $la er therapy! topical therapy of s+in tumors! intrathecal therapy for meningeal isease! an intrapleural rug instillation for malignant pleural effusions" Intraperitoneal A ministration Intraperitoneal chemotherapy eli#ers relati#ely high oses of a chemotherapeutic agent to the serosal surfaces of the peritoneal ca#ity" The use of soft! in welling peritoneal catheters connecte to a su$cutaneous access port has greatly iminishe the ris+ of catheter* relate infections" Intraperitoneal chemotherapy might $e consi ere when peritoneal metastasis or li#er metastasis is the ominant pattern of failure" It has $een use in a$ ominal neoplasms that emonstrate a$ ominal carcinomatosis or malignant ascites! such as o#arian! colorectal! pancreatic! an gastric carcinomas! retroperitoneal sarcomas! pseu omyxoma peritonei! an a$ ominal mesotheliomas" The epth an rate of iffusion of chemotherapeutic agents through peritoneal serosa an into peritoneal tumor epen s on their si'e! lipi solu$ility! an charge" A large molecule with a low lipi content an a positi#e or negati#e charge will ha#e a lower rate of peritoneal surface a$sorption an a longer exposure to peritoneal surfaces" Drugs for intraperitoneal a ministration shoul ha#e +nown tumorici al acti#ity! low peritoneal permea$ility to maximi'e the uration of peritoneal rug exposure! an rapi plasma clearance" Cisplatin is one of the most commonly use agents" The rug must $e e#enly istri$ute throughout the peritoneal ca#ity to optimi'e exposure an pre#ent excessi#ely high rug concentrations in focal flui loculations"

3(ual rug istri$ution re(uires the a$sence of a hesions! necessitating the a ministration of therapy perioperati#ely an a uration of therapy limite to ays" A itionally! stu ies of peritoneal ca#ity flui istri$ution after transperitoneal catheter infusion using water* solu$le contrast or ra ionucli es ha#e emonstrate the nee for instillation of / to 9 liters of crystalloi to assure e(ual istri$ution" Intraperitoneal chemotherapy has $een in#estigate for se#eral years in the treatment of minimal resi ual isease in o#arian carcinoma! $ut an o#erall sur#i#al a #antage has $een ifficult to emonstrate $ecause of the lac+ of ran omi'e ! controlle clinical trials" The efficacy of this therapy in other intraa$ ominal! a$ ominal! an pel#ic malignancies is un er in#estigation" The i eal setting for intraperitoneal chemotherapy is at the time of laparotomy or laparoscopy in a patient with positi#e peritoneal cytology o$taine $y la#age" Intraperitoneal chemotherapy is a goo option for patients with smaller tumor masses or patients at high ris+ for recurrence" Regional Artery A ministration Regional arterial rug therapy to specific organ sites has $een use for se#eral primary an metastatic soli tumors! inclu ing hea an nec+ carcinomas! primary an recurrent gastrointestinal an pel#ic malignancies! extremity sarcomas! in*transit metastatic melanoma! an primary or metastatic hepatic tumors" )im$ perfusion in extremity melanoma employs #ascular isolation of an affecte extremity through external iliac or axillary arterial an #enous cannulation an placement of a proximal lim$ tourni(uet to minimi'e systemic rug lea+age" A high concentration of rug with or without lim$ hyperthermia then can $e perfuse o#er approximately / h an extracte #ia an extracorporeal ialysate pump oxygenator $efore reesta$lishment of normal lim$ perfusion" The maximal rug osage is limite $y lim$ tissue toxicity an not $y systemic rug le#els! an the proce ure is accompanie $y the consi era$le a itional mor$i ity associate with operati#e lim$ #ascular access an compromise woun healing" Chemoem$oli'ation! use in the treatment of primary hepatomas or neuroen ocrine tumors that ha#e metastasi'e to the li#er! eli#ers rug* impregnate pellets or sponge spheroi s that temporarily or permanently occlu e en *arteries selecti#ely supplying tumor*$earing li#er! slowing tumor $loo flow! an increasing the time of rug exposure to the tumor" The same ecrease in flow has $een accomplishe with internal or external! surgically place ! temporary hepatic artery occlusion catheters! which can $e manipulate to cause tumor ischemia after hepatic arterial infusion of rug" The high tissue extraction of some rugs $y hepatic parenchyma has also $een exploite " The fluoropyrimi ines emonstrate high hepatic extraction! with remo#al of more than 90 percent of floxuri ine .4U R0 an %& to ?& percent of &*4U on a single pass after hepatic artery $olus infection" Clinical trials using hepatic arterial 4U R ha#e emonstrate that $iliary sclerosis .apparently irre#ersi$le0 an ele#ation of hepatic en'ymes represent the ose*limiting toxicities seen with hepatic intraarterial 4U R a ministration" Drugs such as oxoru$icin an mitomycin C that ha#e some emonstrate tumorici al acti#ity against primary hepatomas an metastatic colon carcinoma may

also $e gi#en $y hepatic arterial infusion" 6ystemic toxicity! howe#er! $ecomes ose* limiting $ecause the hepatic extraction of these rugs is approximately 9& percent an /9 percent! respecti#ely" Attempts to increase the extracorporeal extraction of these an other rugs from the #enous effluent of the li#er an other regional infusion sites is un er in#estigation using regional #enous filtration techni(ues" 2easuring Response The clinical response to a 5u#ant chemotherapy for micrometastatic isease is etermine $y the rates of recurrence! isease*free sur#i#al! an o#erall sur#i#al" The clinical response to in uction or neoa 5u#ant chemotherapy for #isi$le! palpa$le! or ra iologically measura$le tumors is etermine $y the change in tumor mass" A partial response is generally a &0 percent or greater re uction in summe measura$le tumor mass" 3ach tumor mass is measure as the pro uct of the two greatest perpen icular iameters" A partial response is occasionally su$ i#i e into minor responses .less than &0 percent si'e re uction0 an ma5or responses .more than &0 percent si'e re uction! $ut less than a complete response0" This su$ i#ision is clinically insignificant $ecause only a complete response has the potential for cure" A complete response re(uires total isappearance of tumor on physical examination an ra iologic stu ies for at least ; wee+s" A complete clinical response is li+ely to $e followe $y early relapse if chemotherapy is not continue long enough to eliminate any micrometastatic isease" Tumor progression is efine as a greater than &0 percent increase in summe measura$le tumor mass" 6ta$le isease in icates no change in tumor mass! si'e re uction less than a partial response! or any increase in si'e less than progression" )ac+ of change in tumor si'e oes not always in icate a lac+ of tumor response" 2any large tumors may un ergo necrosis! fi$rosis! or granuloma formation with mar+e estruction of #ia$le tumor cells! $ut minimal or no change in si'e" The increasing use of neoa 5u#ant chemotherapy has ena$le histologic e#aluation of pretreate tumor an normal tissue" The $iologic tumor response to chemotherapy is estimate $y the percentage of #isi$ly unaffecte tumor cells i entifie through histologic examination of sectione tumor" 6i e 3ffects an Toxicity 6ome egree of rug toxicity uring the a ministration of chemotherapy is not only expecte $ut often is esira$le $ecause it in icates a cellular amage response" Aith rare exceptions! the maximal tolerate ose of most chemotherapeutic agents is sought to achie#e the highest tumor cell +ill" Close attention to normal tissue in5ury is essential to optimi'e the ris+N$enefit ratio an assure that the treatment is not worse than the isease" <atterns of organ toxicity ha#e $een well escri$e for the ifferent classes of rugs .Ta$le 9*9?0" The egree of toxicity epen s on rug concentration! uration of exposure! an host response" Anticipate rug toxicity is $ase on the nonspecific amage cause $y most chemotherapeutic agents to rapi ly proliferating normal tissues! such as $one marrow stem cells! gastrointestinal crypt lining cells! an hair follicles" Aithin the same class of rugs! ifferential organ in5ury may $e seen" Rare i iosyncratic systemic rug reactions within any rug category may cause unexpecte an occasionally life*threatening toxicity"

O$5ecti#e an su$5ecti#e measurements of toxicity are serially recor e to allow the eli#ery of maximal tumorici al rug oses with minimal an re#ersi$le in5ury to normal tissues" The 3astern Cooperati#e Oncology =roup .3CO=0 an other groups ha#e e#elope scales that attempt to stan ar i'e toxicity criteria for measurement an reporting in clinical trials" The se#erity of signs! symptoms! an alterations in la$oratory tests are gra e for all ma5or organ systems" =ra e 0 enotes no toxicity! an gra e ; usually enotes life*threatening toxicity" The uration! chronicity! an re#ersi$ility of toxicity are also important" Clinical trials often ha#e pro#isions for ose re uction or cessation of rug therapy for toxicity higher than gra e 9 or :! epen ing on the organ system affecte " Diologic Therapy Diologic therapy is the a ministration of any $iologic molecule or multimolecular complex an inclu es immunotherapy an gene therapy" The most common type of $iologic therapy for cancer is a ministration of recom$inant cyto+ines! such as interleu+in*9 .I)*90 an interferon*alpha .I4N* a0! alone or in con5unction with chemotherapy .$iochemotherapy0" Of increasing interest are cancer #accines! a form of acti#e specific immunotherapy! an gene*$ase inter#entions" Diologic therapy of cancer is generally use in a multimo al regimen to increase the efficacy of surgery! ra iation! or chemotherapy" 4or example! $iologic agents may $e a ministere preoperati#ely to patients with measura$le an surgically resecta$le metastatic isease7 this allows the clinician to etermine clinical response in a measura$le tumor! compare pathologic response to clinical response! an examine the in #i#o effects of $iologics on host*tumor relationships" Alternati#ely! $iologic agents can $e a ministere after curati#e resection to estroy resi ual micrometastatic isease an pre#ent recurrence" Consi era$le effort has $een e#ote to immunotherapy of cancer" Immunotherapy assumes that cancer progression results from failure of the host immune efenses to recogni'e an re5ect the tumor" Diologic agents augment the immune response with the goal of $lunting tumor progression" Theoretically! the immune system may $e acti#ate or reacti#ate to attac+ an estroy tumor specifically! lea#ing normal tissue largely unaffecte " Implicit in the a$ility of the immune system to recogni'e an attac+ neoplastic cells is the existence of immunogenic tumor*associate antigens" 3#i ence that human tumors are immunogenic comes primarily from in#estigations using melanoma! which is one of the most immunogenic soli tumors" Dloo from melanoma patients contains anti$o ies against tumor antigens as well as cytotoxic T cells .CT)0 that can estroy tumor cells in #itro" Clinical stu ies in icate that approximately : to /& percent of all cutaneous melanomas are first iagnose as lymphatic or #isceral metastases without e#i ence of a primary tumor! which suggests that the immune system has cause complete regression of the primary melanoma" 1istopathologic e#i ence of regressi#e changes has $een reporte in up to &? percent of primary melanoma specimens" On rare occasions! there has $een spontaneous! complete regression of metastatic isease" In most experiences! in uction of antitumor anti$o y affor s little protection" In ro ent mo els! immunity to soli tumors cannot $e transferre to normal syngeneic hosts using serum or purifie anti$o y preparations" Dy contrast! T lymphocytes play a critical role in the re5ection of soli tumors in these mo els" In a ition to the

a opti#e specific immunity affor e $y T lymphocytes! natural +iller .N,0 cells can lyse a wi e #ariety of tumor an #irus*infecte cells without the antigen*specific receptors use $y T or D cells" Rapi ly emerging a #ances in the $asic mechanisms of cell*me iate immunity pro#i e new strategies for $iologic therapy $ase on the prospect that the host immune system may $e manipulate either in #i#o or ex #i#o to re5ect neoplastic outgrowth" 2olecular $iology an cell cloning ena$le in#estigation of a new le#el of the $iology of host*tumor relationships an e#elopment of $iologic agents to a minister to cancer patients" No single possi$ility has uni#ersal application! $ut as our un erstan ing of the host immune response to autologous tumor antigens in #arious neoplastic iseases impro#es! the strategies for $iologic approaches to treatment will impro#e #astly" Recom$inant Cyto+ines Ta$le 9*99 lists the cyto+ines currently in use for $iotherapy of cancer" 3arly trials with nonrecom$inant interferon in patients with a #ance melanoma emonstrate a ma5or response rate of /;"; to 99"@ percent" 6u$se(uent trials using recom$inant I4N* a for metastatic melanoma showe a ma5or response rate of a$out 9: percent .range /; to 9? percent0" I)*9! the T cell growth factor! in uces a ma5or response! particularly in patients with metastatic melanoma an metastatic renal cell carcinoma! $ut not in patients with $reast cancer! colon cancer! or lymphoma" The treatment of melanoma was significantly change when ,ir+woo an associates reporte that high* ose I4N*a*9$ significantly prolonge $oth relapse*free an o#erall sur#i#al rates after surgical resection of high*ris+ primary melanoma .American Boint Committee on Cancer .ABCC0 stage II*D0 or regional lymph no e metastases .ABCC stage III0" I4N*a*9$ a ministere intra#enously .90 million UNm9N ay0 for ; wee+s an then su$cutaneously ./0 million UNm9 three times a wee+0 for ;? wee+s increase me ian isease*free sur#i#al $y / to /"% years an me ian o#erall sur#i#al $y 9"? to :"? years! compare with o$ser#ation" Interferon treatment also increase the rate of &*year sur#i#al $y 9; percent" This important stu y was the first ran omi'e controlle trial to show a significant $enefit of a 5u#ant therapy in prolonging relapse*free an o#erall sur#i#al of high*ris+ melanoma patients" On the $asis of the results of the stu y! the 4oo an Drug A ministration appro#e I4N*a*9$ for postoperati#e a 5u#ant therapy in melanoma patients at high ris+ of systemic recurrence" The intra#enous a ministration of the cyto+ines is not without significant toxicity! howe#er! an it is clear that they trigger a casca e of effects that results in other lymphocyte acti#ities as well as the irect effects of I)*9 on other tissues" 6ome of the si e effects are similar to those seen with septic shoc+" Concern o#er the toxicity of intra#enously a ministere cyto+ines has promote the e#elopment of metho s to target cyto+ines an re uce systemic effects" Cyto+ines are a ministere aggressi#ely an fre(uently $ecause of their short half*life in the $loo " In a ition! cyto+ines are not always istri$ute to all areas of the $o y an often o not tra#erse the $loo * $rain $arrier" An inno#ati#e approach is the incorporation of interferon an a 5u#ants into liposomes that irect the cyto+ine to a specific host cell population" In animal mo els! liposomes are ingeste $y macrophages" Degra ation of the Fpac+age G

therapy results in intracellular release of a 5u#ants! such as muramyl tripepti es .2T<*<30! an the interferon! which acti#ates macrophages to $ecome cytotoxic against cancers in #itro an in #i#o" A ran omi'e stu y in og osteogenic sarcoma showe significantly greater response an sur#i#al rates in animals that recei#e the 2T<*<3 liposomes as compare with those that recei#e empty liposomes" This no#el approach has $een exten e to human stu ies! $eginning with a pilot stu y of patients with osteogenic sarcoma an melanoma" Com$ination $iologic therapy is now in clinical trials for treatment of most ma5or human cancers" The multiagent concept is plausi$le $ecause8 ./0 multiple immune a$normalities are most li+ely to occur in cancer patients7 .90 there is heterogeneity in immune response .nature of lymphocytes! role of anti$o y! presence of macrophages0 relati#e to the site of the metastases7 an .:0 com$inations of agents with ifferent mechanisms of action are more li+ely to augment in i#i ual aspects of immune response a iti#ely or synergistically in a i#erse population of cancer patients" 4or example! com$inations of I)*9 an I4N*aelicit a higher rate an more ura$le response time for metastatic melanoma than either cyto+ine alone" Com$inations of tumor antigen! lympho+ines! an cyclophosphami es are inten e to acti#ate tumor* specific immunity! promote effector T cell proliferation! an own*regulate suppressor T cells" Diochemotherapy uses cyto+ines such as I)*9 an I4N*a in com$ination with chemotherapeutic agents such as &*4U with the goal of enhancing antitumor acti#ity" Carious $iochemotherapeutic regimens are $eing examine in patients with metastatic colorectal cancer! lung cancer! renal cell carcinoma! an melanoma" Cyto+ines also ha#e $een use as supporti#e therapy to allow higher oses of chemotherapy" 4or example! granulocyte*macrophage colony*stimulating factor .=2*C640 has $een a ministere with erythropoietin to allow acceleration an ose escalation of chemotherapy with cyclophosphami e! epi oxoru$icin! an &*4U in patients with a #ance $reast cancer" Immunotherapy Immunotherapy is a logical a 5unct for the treatment of su$clinical microscopic isease after efiniti#e cancer surgery! ra iation therapy! or chemotherapy for the following reasons8 ./0 patients who ha#e only small foci of cancer cells remaining after estruction of the ma5or tumor $ul+ are the most li+ely to $enefit from immunotherapy! $ecause the tumor mass that must $e estroye is smallest at that time7 .90 the specificity of the immune response pro#i es a possi$le therapeutic tool that has selecti#ity for small num$ers of cancer cells not possi$le with any other therapeutic mo ality7 .:0 patients with isease in earlier stages are more li+ely to respon to immunotherapeutic maneu#ers! since the cancer patient-s general immune competence is greatest when the isease is locali'e an is often impaire after metastasis7 an .;0 immunotherapy shoul complement rather than interfere with currently a#aila$le metho s of cancer therapy" Decause $oth irra iation an chemotherapy are immunosuppressi#e! the use of immunotherapy in com$ination with these therapeutic mo alities must $e carefully controlle " Ta$le 9*:0 escri$es the types of immunotherapy" The rational application of these immunotherapies to human cancer will epen on a $etter +nowle ge of tumor* associate antigens in human neoplasms an metho s for increasing the immune

response against these agents" Their use shoul $e limite to cancer facilities! where the effects of this form of treatment can $e scientifically e#aluate " Acti#e 6pecific Immunotherapy .Cancer Caccines0 The clinical use of cancer #accines was initiate at the turn of the century! prompte $y the success of #accines against infectious isease" Unli+e #accines against infectious isease! which are a ministere prophylactically! cancer #accines are generally a ministere after the a #ent of isease" Doth types of #accine utili'e attenuate whole cells! cell walls! specific antigens! or nonpathogenic strains of li#ing organisms to stimulate the patient-s immune system to fight the isease" The specific goals of acti#e immunotherapy with cancer #accines are to o#ercome the immunosuppression pro uce $y tumor* eri#e factors! to stimulate specific immunity that will estroy tumor cells! an to enhance the immunogenicity of tumor* associate antigens .TAA0" 6e#eral o$ser#ations support the potential #alue of acti#e specific immunotherapy for the treatment of cancer" These inclu e ./0 #accine* in uce immunity against cancer in animal mo els! .90 the regression an era ication of tumors in5ecte irectly with immunostimulants! .:0 occasional regression of nonin5ecte tumors after the intralesional in5ection of $acille Calmette*=u Urin .DC=0! an .;0 the e#elopment of antitumor anti$o ies" The goals of acti#e immunotherapy are to com$at the ecreasing immunocompetence that results from interaction of tumor*relate pro ucts with components of the immune system an to eliminate the i#erse clones within a tumor cell population $y augmenting cellular an Nor humoral immunity" Unli+e chemotherapy! #accine immunotherapy has no irect cytotoxicity on tumor cells7 its clinical effect epen s on the immune system an is slower in onset $ut ten s to $e more ura$le .Ta$le 9* :/0" A opti#e Immunotherapy In a opti#e immunotherapy! immune lymphoi cells are transferre to a recipient to me iate tumor estruction" Rosen$erg an colleagues pioneere the stu y of a opti#e immunotherapy using lympho+ine* acti#ate +iller .)A,0 cells! which are cytolytic lymphocytes generate in the presence of I)*9" These cytolytic cells can +ill a wi e range of fresh an culture human cancer cells! $ut not normal cells" 1uman )A, cells o not ha#e T cell mar+ers an are not 21C* or antigen*specific in their +illing" Clinical trials using autologous )A, cells .o$taine $y repeate leu+opheresis an in #itro I)*9 expansion0 an systemically a ministere I)*9 pro uce clear! o$5ecti#e responses in some patients with $ul+y metastatic cancer" 6ome e#i ence suggests that )A, cells may $e more important in renal cell carcinoma than in melanoma" 6u$se(uently! the metho was e#elope for isolating tumor*infiltrating lymphocytes .TI)0 from human melanoma an renal cell carcinoma7 after proliferation ex #i#o in the presence of I)*9! the TI) were returne to the patients an I)*9 therapy a ministere concurrently" In preliminary stu ies! response rates of up to ;0 percent were o$taine " Unli+e )A, cells! the TI) may ha#e an important role in the therapy of local an regional isease! while )A, cells may remain useful in the treatment of hematogenous issemination an some renal cell carcinomas" TI)*$ase

immunotherapy is an acti#e area of research! an TI)s also are $eing in#estigate in con5unction with gene therapy" Nonspecific Immunotherapy Certain su$stances! such as mixe $acterial toxins an fractions of the tu$ercle $acillus! nonspecifically enhance host resistance to most #iral! fungal! an $acterial agents" Although the exact mechanism is un+nown! these agents appear to stimulate immune response to a wi e #ariety of antigens! inclu ing tumor antigens" Interest in a nonspecific immunotherapy was re#i#e more than 90 years ago using attenuate $o#ine tu$erculosis $acillus .$acille Calmette*=uUrin! DC=0" 6ome tumor regressions were o$ser#e ! $ut consistent responses in any one treatment group were ifficult to achie#e" There are se#eral possi$le mechanisms to explain tumor regression following DC= in5ection7 specific an nonspecific immune reactions were pro$a$ly in#ol#e " The tumor cells may $e +ille as Finnocent $ystan ersG uring the elaye cutaneous hypersensiti#ity reaction that occurs when lymphocytes an macrophages attac+ DC= isperse throughout the tumor no ule" This is supporte $y the o$ser#ation that the intratumor in5ection of DC= wor+s only in patients who can $e sensiti'e to DC=! as shown $y their elaye cutaneous hypersensiti#ity reaction to purifie protein eri#ati#e" In a ition to the nonspecific effect! a specific immune response to melanoma* associate tumor antigens occurs in some patients $ecause an associate rising titer of antimelanoma anti$o y is o$ser#e after DC= immunotherapy" 6e(uential $iopsies of tumor no ules ta+en after DC= inoculation re#eal that the regression of these no ules is associate with granulomatous infiltration of lymphocytes! monocytes! an fi$ro$lasts surroun ing an infiltrating the melanoma cells" The regression of melanoma no ules not in5ecte with DC= is accompanie $y the appearance of lymphocyte infiltrates within the regressing melanoma tumor no ules" The specific antitumor effect may result from more lymphocytes an macrophages coming into contact with the tumor cells an promoting antigen presentation" Con#ersely! it may wor+ #ia the effector lim$ of the immune response $y $ringing greater num$ers of stimulate an unstimulate lymphocytes to the tumor" Other nonspecific agents inclu e Coryne$acterium par#um! Dor etella pertussis! 2T<*<3! methanol*extracta$le resi ue of DC=! $acterial en otoxins! an polynucleoti es" Another form of nonspecific immunotherapy in#ol#es the use of agents capa$le of restoring epresse immune responses" 6e#eral agents ha#e $een propose ! inclu ing thymic hormones! such as thymosin! an the antihelmintic rug le#amisole" <assi#e Immunotherapy The systemic use of tumor*specific antiserum is la en with theoretical an practical pro$lems" <assi#e immunotherapy is effecti#e only in suppressing small num$ers of tumor cells an must wor+ in concert with host effectors .e"g"! complement! macrophages! antigen* epen ent cellular cytotoxicity0 to effect a cytotoxic action on target cells" In a ition! only anti$o ies of certain classes an su$classes can interact effecti#ely with certain cellular effectors" 2ost of the $etter*characteri'e human tumor*specific antisera are murine monoclonal anti$o ies that! $ecause of their antigenicity! ha#e limite applications in human $eings"

Immunotoxins are tumor*specific anti$o ies that are attache to toxic molecules" This concept! first propose $y 3hrlich a century ago! uses the anti$o y molecule to preferentially locali'e anticancer agents in the #icinity of tumors" It o$#iates the nee for the host to supply effector cells or complement to me iate tumor estruction" 2onoclonal anti$o ies are preferre to heterologous antiserum $ecause they permit the use of homogeneous! purifie anti$o ies of efine specificity" A wi e range of toxic molecules has $een teste in #itro an inclu es ra ioacti#e isotopes! tra itional cancer rugs! an plant an $acterial toxins" Recom$inant DNA technology now permits the creation of hy$ri or chimeric immunotoxin molecules in which the 4c fragment of the immunoglo$ulin molecule has $een replace $y a polypepti e toxin se(uence" Immunotoxins are currently un ergoing clinical trials! although their o#erall therapeutic efficiency in clinical oncology is unpro#e " =ene Therapy =ene cloning has intro uce a new era of $iologic therapy that will ha#e an impact on human clinical trials in the coming years" An example is the stu ies $y 1ellstrom an colleagues! in which a clone gene for one of the ma5or human melanoma tumor* associate antigens .p9%0 was intro uce into the genome of a #accinia #irus" The #irus then expresse $oth immunogenic #iral antigens! plus the wea+er immunogenic human melanoma antigens on the surface" This reagent will $e teste in human stu ies in the near future" A no#el approach is transfection of human TI) with genes for pro ucing cyto+ines! such as tumor*necrosis factor .TN40" The a$ility to transfect cyto+ine genes into human TI) suggests a apti#e cellular therapy with genetically transfecte cells capa$le of pro ucing high concentrations of tumor*necrosing factor or other lympho+ines at the tumor site" This woul eli#er high concentrations of cyto+ine to the tumor site while sparing the #ascular compartment of the otherwise eleterious effects of high* ose! systemic cyto+ine" =ene transfection also may $e use to augment the immunogenicity of tumor #accines" <reclinical stu ies emonstrate enhance cellular immunity when whole*cell #accines are transfecte with I)*9! I)*;! I)*%! an Nor =2*C64" 6e#eral phase I an phase II clinical trials of cyto+ine*trans uce cellular #accines for patients with a #ance melanoma are un er way" Other approaches to gene therapy of cancer are antisense oncogene an tumor suppressor gene therapy! which attempt to correct genetic isor ers of cancer $y suppressing the a$normal expression of proliferati#e genes" <otent regulatory antisense DNA se(uences can pre#ent the translation of molecules that own*regulate host immunity to tumor" 2anagement of Distant 2etastases at 6pecific 6ites )ung! <leura! an 2e iastinum Two of the most common initial sites of metastasis are the lungs an pleura" Although pulmonary metastases are generally asymptomatic! they may cause persistent cough! shortness of $reath! an Nor chest pain" An irritating! ry! an unpro ucti#e cough may progress to hemoptysis" A stan ar chest x*ray is sufficiently sensiti#e an cost*effecti#e for screening all cancer patients an fre(uently will re#eal hilar an me iastinal a enopathy in those with pulmonary metastases" Although pulmonary tomograms or CT scans ha#e too

low a yiel an too high a cost to $e 5ustifie when the chest x*ray is normal! they are of #alue in e#aluating suspicious chest lesions or in etermining whether the metastatic isease seen on the chest x*ray is present elsewhere in the chest" Tomograms can etect lesions as small as @ mm in iameter! an CT scans can i entify lesions as small as : mm" Their increase sensiti#ity is offset $y ecrease specificity7 the false*positi#e rate can $e as high as /& percent" The choice $etween the two tests often epen s on a#aila$le facilities! cost! an s+ills of the ra iologist" Neither test is in icate unless the presence of pulmonary metastases woul alter the treatment plan or unless a $etter efinition of lesions is re(uire for entry into a research protocol" Dronchoscopy with $iopsy may $e consi ere when the etiology of a pulmonary lesion is in ou$t .e"g"! metastatic isease! fungal isease! $enign tumor! or $ronchogenic carcinoma0! especially when symptoms suggest $ronchial in#ol#ement .e"g"! a pro ucti#e cough or a centrally place or ca#itary lesion0" A scalene lymph no e $iopsy is in icate for palpa$le no es" 2e iastinoscopy is in icate if the chest x*ray! tomogram! or CT scan re#eals a$normal me iastinal no es that are accessi$le through the instrument" Thoracentesis or pleural $iopsies may $e helpful when e#aluating effusions" 4ine*nee le $iopsy of a pulmonary lesion un er CT scan gui ance may $e useful in selecte instances to esta$lish the histologic iagnosis" Ci eo*assiste thoracoscopy is increasingly use $oth iagnostically an therapeutically in the staging an treatment of lung cancer" This techni(ue permits #isuali'ation of the entire #isceral! parietal! an me iastinal pleural surfaces an excisional or incisional $iopsy for esta$lishing iagnosis" If the iagnosis remains in ou$t! an exploratory thoracotomy may $e necessary! especially for a solitary lesion! $ecause some patients will ha#e potentially cura$le primary lung cancer" The treatment approach is etermine $y the location an num$er of thoracic metastases an $y the patient-s o#erall status" Nearly all patients with isseminate cancer e#elop metastases in the chest prior to eath" 6ome neoplasms! such as melanoma! metastasi'e preferentially to the lungs" 6urgical resection may $e in icate e#en when there is more than one pulmonary metastasis" In most surgical series! the me ian sur#i#al is /% months! with a &*year sur#i#al rate of 90 to 9& percent" 6ome patients li#e more than /0 years" Resection of a solitary pulmonary metastasis pro#i es a higher rate of &*year sur#i#al than resection of primary $ronchogenic carcinoma of the lung" Criteria for resection inclu e a$sence of metastases at other sites! control of the primary tumor! potential for complete resection! an a long tumor ou$ling time" CT scans shoul $e o$taine preoperati#ely $ecause the num$er of lesions emonstrate $y CT scanning is often greater than that shown $y chest x*ray" )ung parenchyma shoul $e conser#e uring resection" 2ost metastases occur 5ust $elow the pleura! an a we ge of tissue remo#e $y segmental resection suffices" 6tapling! electrocautery! an laser surgery can $e useful" )o$ectomy an pneumonectomy usually are not in icate " <atients who are ineligi$le for surgery! such as those with multiple slow* growing tumors! might $e monitore $ut recei#e no treatment while they are asymptomatic" If the pulmonary metastases progress rapi ly! chemotherapy can $e consi ere ! especially if multiple #isceral metastases exist at other sites or if the patient has isease symptoms" A pleural effusion associate with lung cancer oes not rule out resection7 malignant pleural isease must $e ocumente " If patients are symptomatic!

they can $e treate $y thoracentesis! tu$e thoracostomy! or thoracoscopy with chemical pleuro esis" Close chest tu$e rainage an sclerosis often are necessary for effecti#e control of recurrent symptomatic effusions" Talc ilute in normal saline solution is the agent of choice for chemical pleuro esis" Talc can also $e eli#ere #ia #i eo*assiste thoracoscopy" 4e#er is a common si e effect! an chest pain! yspnea! an pulmonary infiltrates sometimes occur" <leural effusions are generally associate with a short sur#i#al time" Tumor Dou$ling Time The growth rate of a tumor can $e expresse $y the time the tumor ou$les in #olume" The tumor ou$ling time .TDT0 is an accurate an repro uci$le measure of $iologic aggressi#eness that can $e use to etermine the in ications for surgical resection" TDT represents the $alance $etween the intrinsic proliferati#e rate of the tumor cell an the patient-s immune efense mechanisms" TDT measurement is especially useful in treating patients with pulmonary metastases $ecause neoplasms ten to $e peripherally locate an iscretely i entifie on chest ra iographs" It is (uite easy to o$tain accurate serial chest x*rays that can $e use to measure the changing iameters of the lesion" The greater an lesser iameters are a#erage an then plotte against time on semilogarithmic paper" The slope of the line rawn $etween any two points represents the rate of tumor growth" The hori'ontal istance $etween any two ou$ling points represents the TDT in ays" TDT may #ary from ? to @00 ays! $ut most tumors ou$le in 90 to /00 ays" <atients with a short TDT ha#e aggressi#e! fast*growing metastatic lesions7 patients with a long TDT might ha#e nonaggressi#e lesions that woul $e responsi#e to surgery" TDT is an important prognostic tool for selecting surgical can i ates" TDT also can $e use to monitor the effects of chemotherapeutic agents an compare ifferent therapeutic regimens" <atients with pulmonary metastases can $e i#i e into three sur#i#al groups accor ing to TDT" Those patients with TDT less than 90 ays are not recommen e for surgery7 it is li+ely to $e ineffecti#e an will not result in long*term sur#i#al" <atients with a TDT of 90 to ;0 ays are not ineligi$le for surgery! particularly if a slowing of TDT is o$ser#e after preoperati#e chemotherapy7 their long*term sur#i#al rates are not much impro#e $y surgery alone" <atients with a TDT of ;0 ays or more can ha#e long*term sur#i#al after resection of the pulmonary lesion" 6arcoma patients with a TDT of more than ;0 ays were foun to ha#e significant palliation from pulmonary resection an remaine free of isease for as long as & years7 patients with a TDT of less than 90 ays i not significantly $enefit from resection of metastatic lesions" )i#er! Diliary Tract! an 6pleen 1epatic metastases can occur in many patients with metastatic isease! especially those with gastrointestinal malignancies an $reast cancer" There are no relia$le an accurate tests for early etection of li#er metastasis! an no common symptoms an physical signs" The patient might experience ecrease appetite with loss of weight followe within wee+s $y general lassitu e an e$ility" The loss of appetite can prece e a clinically palpa$le li#er $y a month or more" Con#ersely! the patient may ha#e an easily palpa$le li#er an feel perfectly well" As the li#er isease progresses! nausea! #omiting! 5aun ice! night sweats! an fe#er can e#elop"

A history an physical examination an serum li#er chemistries with appropriate tumor mar+ers are the most cost*effecti#e screening tests" 3le#ate le#els of lactic ehy rogenase or al+aline phosphatase in the presence of normal or only slightly ele#ate le#els of serum glutamic* oxaloacetic transaminase or $iliru$in suggests li#er metastasis" An ele#ate lactic ehy rogenase le#el is a clinically useful an relati#ely specific in icator for metastatic melanoma" 6uspecte li#er metastasis shoul $e confirme $y ultrasonography! ynamic CT scan! or CT portography" Ra ionucli e li#er scanning an hepatic arteriography are less fre(uently use " The choice epen s on the a#aila$ility an cost! the interpreti#e s+ills of the ra iologist! an the generation of e(uipment use ! which is especially important in CT scanners an ultrasoun units" A$ ominal CT scans are more accurate an relia$le than ultrasonography an ra ionucli e li#er scans for e#aluation of li#er masses" <3T scans also are increasingly useful in etecting metastatic isease" 1epatic metastases are not etecte $y ra iologic tests until they are more than / cm in iameter" Angiography is use only when the ifferential iagnosis cannot $e esta$lishe $y nonin#asi#e techni(ues! when the information gaine woul affect the treatment ecision! or when hepatic resection is contemplate " Diopsy usually is not necessary to confirm the iagnosis of li#er metastasis" In the few instances in which $iopsy confirmation is essential to treatment ecisions! a nee le $iopsy can $e performe percutaneously with CT or ultrasoun gui ance! or $y laparoscopy! or uring laparotomy" 6ome patients with isolate li#er metastases from colorectal cancers can $enefit from surgical resection" Those patients with a solitary metastasis or metastases locate in one lo$e are often successfully treate with resection! an approximately 9& percent will sur#i#e for & years" 2ost li#er metastases are not amena$le to surgical excision" 6ystemic chemotherapy or hepatic arterial chemotherapy is the most common inter#ention for patients with nonresecta$le hepatic metastasis! an response rates #ary" Cryosurgery might offer effecti#e palliati#e treatment for patients with nonresecta$le primary or metastatic hepatic malignancies7 in certain cases! exten e sur#i#al has $een reporte with the potential for cure" Other treatments inclu e hepatic artery em$oli'ation! chemoem$oli'ation! ra iation therapy! an alcohol in5ection" Drain an 6pinal Cor 2any cancers! particularly $reast cancer! lung cancer! an melanoma! metastasi'e to the $rain! a common cause of eath" 1ea ache an mental eficits are the most common symptoms of $rain metastasis" 1ea ache resulting from $rain metastasis characteristically $egins as a mil morning hea ache" As the con ition progresses an the intracranial pressure increases! the hea ache will persist longer into the ay an $ecome more se#ere" It is usually generali'e ! $ut it may $e slightly worse in the frontal or occipital region an is sometimes associate with #isual changes" The most common physical sign of $rain metastasis is a focal neurologic eficit7 sei'ures are common" The presence of papille ema is a helpful sign! $ut its a$sence is not useful iagnostically"

The $est tests for iagnosing intracere$ral metastasis are 2RI an CT with contrast enhancement" 2RI! a techni(ue that epen s on the intrinsic paramagnetic properties of $iologic tissue! is generally the preferre test to etect an stage $rain an spinal metastases" 2RI can etect tumors that cannot $e etecte $y CT scans" 2RI has an a #antage particularly for lesions at the $ase of the s+ull an in the posterior fossa! $ecause only a wea+ signal is generate from the a 5acent $one" 2RI scans appear to ha#e a higher tissue sensiti#ity! inclu ing a $etter a$ility to istinguish hemorrhage from tumor! than CT scans" The accuracy an sensiti#ity of these scans ma+e it unnecessary! in most cases! to perform a ra ionucli e $rain scan or electroencephalogram unless there are some e(ui#ocal fin ings" A caroti arteriogram may $e in icate to rule out #ascular a$normalities" A lum$ar puncture an cere$rospinal flui analysis to iagnose meningeal in#ol#ement occasionally is necessary .after a CT scan0 for a patient who has a cranial ner#e palsy! $la er ysfunction! or nonlocali'ing or $ilateral neurologic signs an symptoms" The mainstay of initial treatment is corticosteroi s! the most effecti#e of which is examethasone .up to /00 mgN ay0" Dexamethasone re uces e ema aroun the tumor an temporarily helps to relie#e symptoms in the ma5ority of patients" The steroi ose shoul $e tapere o#er 9 to ; wee+s as tolerate an the therapy stoppe after efiniti#e treatment unless the patient-s symptoms intensify uring steroi with rawal" 6teroi s often o not help patients with rapi neurologic eterioration $ecause this con ition usually reflects intracere$ral hemorrhage aroun the metastasis" Chemotherapy is not usually effecti#e for $rain metastasis" 6urgical excision followe $y cranial irra iation is the treatment of choice for a solitary! surgically accessi$le metastasis" Tumor excision $y means of a craniotomy is relati#ely safe7 it alle#iates symptoms in most patients an pre#ents further neurologic amage in patients with emonstra$le metastases" The treatment may $e consi ere in some patients who ha#e isease at other sites plus symptomatic $rain metastases $ecause their estimate life span can excee : months! an their neurologic status usually impro#es" <atients treate with open $rain surgery an fractionate ra iotherapy ha#e a $etter outcome than those treate with ra iation alone! $ut many patients o not ha#e surgically accessi$le cere$ral metastases" In these cases! stereotactic ra iosurgery using the Fgamma +nifeG may offer the $est chance of prolonge sur#i#al" Done Done metastases are common in patients with a #ance $reast or prostate cancer $ut infre(uent in patients with gastrointestinal cancers" They are me ullary in location an estructi#e in nature" The pain from $ony metastases is typically nocturnal at first! $ecoming persistent! progressi#e! an locali'e ! an it can $ecome (uite se#ere" Done metastases are fre(uently iagnose in symptomatic patients! $ut occasionally they are seen inci entally on ra iographs .e"g"! ri$ metastases on routine chest x*ray0 or a $one scan prompte $y an ele#ate serum al+aline phosphatase le#el in the a$sence of li#er metastasis" They are generally osteolytic in appearance on

ra iography an pro#o+e little if any $one formation! $ut some patients with prostate cancer ha#e osteo$lastic $one metastases" Axial metastases account for up to ?0 percent of $ony lesions an are most common in the spine an ri$" Ahen $ony lesions in#ol#e the #erte$ral $o y! there are often compression fractures that may lea to neurologic symptoms! such as ra icular $ac+ pain! paresthesia or paresis of the legs! an urinary retention" Only a$out /0 percent of lytic lesions occur in weight*$earing $ones! $ut these coul result in pathologic fractures" The ra ionucli e $one scan is the initial test for e#aluating suspecte $one metastases" Its sensiti#ity is reporte ly &0 to ?0 percent greater than ra iographs alone! $ut $one scan a$normalities are nonspecific an must $e correlate with ra iographic stu y .x* ray or CT scan0 an patient history .fractures! trauma! arthritis! etc"0 to istinguish $etween $enign an malignant causes" A $one $iopsy might $e necessary to esta$lish the iagnosis $efore instituting treatment" The treatment of $one metastases epen s on the egree of symptoms! the location an magnitu e of the lesions! an the patient-s life expectancy" The goals of therapy are to relie#e pain an maximi'e am$ulation" <atients without symptoms shoul $e monitore to assess the progression of their lesions $ut shoul recei#e no ma5or treatment unless they $ecome symptomatic" 6ymptomatic metastases fre(uently in#ol#e non*weight*$earing $ones! particularly the spine an ri$s" In these cases! irra iation of the lesions usually pro#i es relief" The ra iation fiel s shoul $e restricte to those lesions responsi$le for the symptoms" 6ymptomatic $one lesions only occasionally respon to systemic chemotherapy! $ut $one metastases from $reast cancer sometimes respon well to hormonal therapy" 6ymptomatic metastases in weight*$earing $ones .e"g"! the femur0 re(uire special consi eration" If the lesion is large! an if there is e#i ence of cortical estruction! prophylactic sta$ili'ation an irra iation are sometimes use when the patient-s life expectancy is at least 9 months" 6ta$ili'ation inclu es operati#e metallic $one fixation .e"g"! with intrame ullary ro s0! 5oint replacement! repair with methyl methacrylate! or external $races or a cast" Ra iotherapy is generally gi#en postoperati#ely" Alternati#ely! the lesion might $e treate with ra iation alone! $ut the patient must $e closely monitore for e#i ence of pathologic fracture" Unless the surgical ris+ is high or the patient-s expecte life span is short! pathologic fracture of a weight*$earing $one shoul $e sta$ili'e ! maximi'ing the patient-s (uality of life an ecreasing hospital or nursing home costs" <atients with fractures of the #erte$rae that ha#e compresse the spinal cor re(uire prompt treatment to a#ert paralysis" The treatment may re(uire ecompressi#e laminectomy an postoperati#e irra iation! or irra iation alone! epen ing on the extent of the isease an the patient-s o#erall me ical con ition" 6+in! 6u$cutaneous Tissues! an Distant )ymph No es These are the most common sites of istant metastases an are often the first sign of hematogenous sprea " 6+in an su$cutaneous metastases generally are 0"& to 9"0 cm in iameter an are rea ily etecta$le $y physical examination" Distant lymph no e metastases can occur in any area" The more superficial no al metastases are easily iagnose $y physical examination" 2etastases within the thorax usually can $e etecte on chest x*ray! with CT scans or tomograms use as confirmatory tests! $ut

a$ ominal no al metastases are generally etecte $y CT or ultrasoun scans" These lesions usually are treate ! especially when symptomatic an isolate ! $y surgical excision .if superficially locate 0 or ra iation therapy" Other treatments inclu e intralesional immunotherapy with DC=! regional chemotherapy .isolate perfusion of the extremities0! or systemic chemotherapy or hormone therapy! especially when there are multiple lesions or simultaneous #isceral metastases" =astrointestinal Tract 6ome cancers! particularly melanoma! can metastasi'e to the gastrointestinal tract! often to multiple sites" 3arly gastrointestinal in#ol#ement usually causes persistent $ut nonspecific complaints! such as epigastric istress! nausea! anorexia! or weight loss" The most common clinical manifestations are the result of chronic $lee ing .anemia! anorexia! an weight loss0! o$struction of the small $owel .a$ ominal pain! nausea! an #omiting0! an acute $lee ing .hematemesis or melena0" 4or example! a patient with melanoma metastatic to the gastrointestinal tract typically presents with a symptom complex of gastrointestinal complaints! guaiac* positi#e stool! an anemia" =astrointestinal metastases are ifficult to etect $y ra iologic stu ies! the routine use of which is not in icate for screening" 4ollow*up clinical examination shoul inclu e a guaiac test of a stool specimen" Although su$5ect to limite specificity! a positi#e result is an in ication for further in#estigational stu ies using $arium enema! colonoscopy! esophagogastro uo enoscopy .3=D0! or CT scans of the a$ omen an pel#is" Newer stu ies! such as <3T scans an ra iola$ele monoclonal anti$o y scans! might $e helpful in i entifying the general location of a metastasis" <ersistent anemia without an i entifie lesion may in icate further stu ies! such as small $owel enteroclysis! ra ionucli e scans! or angiography! with possi$le em$oli'ation to control persistent $lee ing from nonopera$le lesions" Repeate $loo transfusions might $e in icate for persistent anemia in patients who ha#e nonresecta$le #isceral metastases or for whom a thorough wor+up faile to re#eal a source of $lee ing" Chemotherapy can $e consi ere for patients with multiple gastrointestinal lesions! $ut surgical excision shoul $e consi ere for isolate gastrointestinal metastases if the patient-s con ition is goo " 6urgery is recommen e for most patients who ha#e acute complications of o$struction! massi#e $lee ing! or perforation $ecause the alternati#e is to allow the patient to ie" The final ecision epen s on the patient-s o#erall clinical con ition! $ut symptoms can $e successfully alle#iate in most cases! an sur#i#al after surgical excision a#erages ; to ? months" <6>C1O)O=IC 2ANA=323NT AND R31ADI)ITATION The physician can ease the cancer patient-s fear of the isease $y free an open communication" <sychologic support an e ucation are necessary for the patient to eal with any isa$ility that can result from therapy" 3xamples inclu e training in the care of a stoma following curati#e surgery for colonic an rectal cancer an referral to lay groups associate with the American Cancer 6ociety for counseling the anxious patient with an altere $o y image resulting from mastectomy" It is impossi$le to pre ict the exact course of any malignant tumor" <atients with a poor prognosis are occasionally cure $y aggressi#e therapy! an spontaneous regressions are sometimes o$ser#e in patients with metastases" In contrast! some

patients with apparently locali'e isease can ie of isseminate cancer in a few months" Uncertainty a$out the future is one of the most ifficult a 5ustments that cancer patients an their families face" It is reassuring to emphasi'e that the chances for cure impro#e each month after successful treatment of the primary neoplasm! particularly for tumors such as s(uamous cell carcinoma of the lung or oropharynx" Other! more slowly growing neoplasms! such as carcinoma of the $reast an malignant melanoma! can recur after isease*free inter#als of /0 to 90 years! though the chances of recurrence also ecrease with time" Recognition that cancer is a chronic isease is an important aspect of management" )ong*term! consistent follow* up pro#i es opportunities for reassurance an usually can ensure etection of recurrence at an early stage" 6ome patients suspect the worst $ut o not want to hear the truth from their physician" 1owe#er! a lie is ne#er appropriate! e#en if re(ueste $y the family" Untruths often create $arriers $etween patients an their families that can lea to psychologic isolation of patients! who are una$le to iscuss their fears an anxieties with those they nee most" =entle an optimistic truth is generally the $est approach! e#en when primary cancer therapy has faile an the patient is 5u ge incura$le" Realistic an consistent support is actually more important to the patient an family at this stage of the isease than earlier" There is increasing e#i ence that patients tolerate the process of ying much $etter when sustaine $y the physician-s continuing concern an acti#e support" 6ome incura$le patients are una$le to accept the realities of the situation" In this case! it is essential that a responsi$le family mem$er $e informe " The uration of the incura$le patient-s life is so uncertain that pre ictions shoul $e a#oi e " If! as fre(uently happens! the relati#es insist on some estimate! a com$ine minimum* maximum prognosis! such as from @ months to 9 years! will help the family accept this uncertainty" The $asic aim in caring for the patient with a #ance cancer is to prolong useful life! $ut not useless suffering" The patient shoul $e permitte to ie with ignity when acti#e therapy can no longer $e of $enefit" 6UR=3R> IN T13 4UTUR3 Increasing e#i ence suggests that surgery shoul $e the last! rather than the first! therapeutic inter#ention" 6urgery un erta+en after chemotherapy an ra iation therapy can remo#e cancer cells that are resistant to these mo alities" Chemotherapy an ra iation therapy $efore surgery can shrin+ the tumor mass to $e excise an impro#e the possi$ility of organ preser#ation" There ha#e $een promising results from preliminary trials using these concepts in $one an soft tissue sarcomas! locally a #ance $reast cancer! an other neoplasms" 6urgery may $e consi ere a form of immunotherapy" Any therapeutic maneu#er that lowers tumor $ur en can re#erse tumor*associate immunosuppression! altering the immune $alance in fa#or of the patient" Tumor*associate immunosuppression is cause $y antigens she from a growing neoplasm into the $loo an $y humoral factors pro uce $y or in response to the neoplasm" Cancer surgery effecti#ely remo#es the cancer cell mass that pro uces the immuno epression an allows the patient-s immune responses to reco#er" Once the tumor mass has $een remo#e ! the

patient-s immune system can eal with any clinically silent micrometastases" 6urgical resection of apparently locali'e tumors can fa#ora$ly affect the host*tumor relationship an may e#en cure the patient with su$clinical istant metastases" Dy re ucing the num$er of tumor cells! it also increases the curati#e potential of systemic therapies" 3arly Detection In many neoplasms! prognosis epen s on the status of the lymph no e $asin raining the primary tumor" The extent an timing of lymph no e issection is contro#ersial" 6entinel lympha enectomy! a promising techni(ue for early etection of no al isease! is un er in#estigation in multicenter trials" Detection of the sentinel no e .i"e"! the first lymph no e raining a primary tumor0 was intro uce for melanoma an is $eing applie to $reast carcinoma an other neoplasms" Initially the techni(ue relie on in5ection of a #ital $lue ye at the tumor site an #isual trac+ing of this ye along the lymphatics to the no al $asin" 6entinel no e mapping is now facilitate $y a ing a ra iola$ele isotope to the ye an monitoring its path $y a han hel gamma pro$e" Ra ioimmunogui e surgery .RI=60 using murine monoclonal anti$o y .2A$0 ena$les surgeons to locali'e pre#iously un etecte malignant lesions an isseminate isease intraoperati#ely" It is especially effecti#e in locali'ing primary an secon ary colorectal! gastric! an o#arian carcinomas" 4or RI=6! 2A$ is con5ugate to /9&I! which has a half*life of a$out @0 ays" Ra iola$ele 2A$ is a ministere intra#enously approximately 9 wee+s $efore surgery" To a#oi ra ioacti#e upta+e $y the thyroi glan ! a supersaturate solution of potassium io i e is a ministere 9 ays $efore the 2A$ an continue for : wee+s" During surgery! the surgeon manipulates the gamma* etecting e#ice! consisting of a etection crystal! a preamplifier! an a signal processor with a igital rea out" This e#ice pro uces au i$le an numerical isplays as it encounters ra iola$ele tumor cells" It allows the surgeon to efine tumor margins! to see+ out malignant lesions that might ha#e escape pre#ious etection $y CT scan or plain chest x*ray! an to examine thoroughly those sites that might contain tumor cells" .Di$liography omitte in <alm #ersion0

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