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T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Summarizing the Clinical Effects of Smoking on the Cancer Patient

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Summarizing the Clinical Effects of Smoking on the Cancer Patient

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Summarizing the Clinical Effects of Smoking on the Cancer Patient

nan nan

Sm ok i ng by cance r pa ti en t s increases m o rtalit y , t ox icit y , rec u rre n ce , a nd the r is k of a second p rim a r y canc e r . T h ere are f ou r im po rta n t c on cl u si on s , a nd a

T H E C LINICAL E FF ECTS OF SMOKING ON T H E C ANCER PA TI E NT

Summarizing the Clinical Effects of Smoking on the Cancer Patient

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f i f t h im p li ed conc l us i on, t o t he e v i d e n ce p re v i ou sl y p rese n te d : 1. On e o r m o r e adve r se e f f ec ts o f sm ok i ng a f fect all ca n cer d isease site s. 2. On e o r m o r e adve r se e f f ec ts o f sm ok i ng a f fect all treatme n t m od aliti es. 3. Th e e f f ec t s o f cu rr en t s m ok i ng are d isti n ct fr o m a n e v er o r f o rmer sm o ki ng h i s t o r y . 4. Se v e ra l li nes o f ev i dence d em on strate t h at ma ny o f t h e e f fects o f sm o ki ng a r e r eve r s i b l e. A lt hough subs t an ti a l da t a d em on strate t h at sm ok i ng by ca n cer p atie nts i n c r ease s t he ri sk f o r one o r m o re ou tc o mes , t h e lar g est limitati on s are t he lac k of st anda r d t obacco use defi n iti on s , t h e lac k o f assessi ng t ob acc o use in ca n ce r p ati en t s a t f o ll ow - up, a nd t h e lac k o f str u ct u re d t ob acc o cessati on f o r ca n ce r p ati en t s. Im po rt an tl y , p atie n ts ma y f u rt h er misre p rese n t t ob acc o use. Se v e r al s t ud i es sugges t t ha t app r ox imatel y 30 % o f ca n cer p atie n ts w ho sm ok e d e ny t obacco use . , Mari n et al . e x em p lif y t h e im po rta n c e o f a n acc ur at e assess m en t , de m o nstrati ng t h at p atie n ts w ho self-re po rte d sm ok i ng had no s i gn ifi can t ri sk ass o ciate d wit h s u r g ical c o m p licati on s; how e v e r , b i oche mi ca l con firmati on o f sm ok i ng si gn ifica n tl y i n crease d t he r is k of s u r g i ca l wound co m p l i cati on s . T h is h i gh li gh ts t h e po te n tial d isc r e p a ncy be t ween t he e f f ec ts o f sm ok i ng b ase d on s ub jecti v e v ers u s b i o c h e m i ca ll y con firm ed asse ssme n ts . D u e t o t h is d iscre p a n c y , t h e fift h i mp lie d conc l us i on i s t ha t t he a dv erse e f fects o f sm ok i ng a nd t h e b e n efit s o f cessati on m ay be m o r e p r onoun ce d t h a n c u rre n tl y re po rte d i n t h e literat u r e.

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

National Oncology Association Statements and Clinical Practice Guidelines

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P rof essi ona l soc i e ti es a r e t ak i ng lea d ers h i p r o les i n rec ogn izi ng t h e n ee d to assess p ati en t s ’ t obacco use and t o e x ami n e t h e effects o f t ob acc o u se i n

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Smoking Cessation Guidelines

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Ov e r all , t he app r oach t o t obac c o cessati on f o r t h e ca n cer p atie n t is v er y simila r to t he app r oach f o r t he g e n eral popu lati on. H o we v e r , t h ere are a f ew s p eci f ic de t a il s t ha t a r e im po rta n t t o c on si d er w h e n a pp r o ac h i ng t h e ca nce r p atie n t who s m okes. It i s im po rta n t t o rec ogn ize t h at v irt u all y all n ewl y d ia gno se d cance r pa ti en t s a r e face d wit h a life-c h a ng i ng d ia gno sis t h at will r e qu i r e int ens i ve tr ea tm en t ap pr o ac h es . T reatme n ts , t ox icit y , a nd ou tc omes d i f f e r ac co r d i ng t o d i sease s ite a nd treatme n t m od alit y . W h ereas s o me ca n ce r p ati en t s m ay have a c ura b le ca n ce r , o t h ers ma y h a v e i n c u ra b le ca n ce r . Sm ok i ng i n cance r pat ie n ts is als o o fte n ass o ciate d wit h c o m o r b i d p s y c h iatri c d i seases, such as d e p ressi on, t h at ma y affect d e p e nd e n ce . The u r g e n c y o f cessa ti on i s a l so im po rta n t t o c on si d e r . If sm ok i ng d ecreases the e f f icac y o f cance r tr ea tm en t , t h e n e v er y eff o rt s hou l d b e ma d e t o st op t ob acc o u se as soon as poss i b le rat h er t h a n c hoo si ng a qu it d ate se v eral w ee k s o r m on t hs a ft e r a canc er d ia gno sis . Patie n ts ma y als o b e bu r d e n e d w it h a “sti g m a” assoc i a t ed w i th certai n t ob acc o -relate d ca n cers , – w he r e t h e y ma y be v i ewed by o t he rs , o r t h emsel v es , as ca u si ng t h eir ca n cer du e to t ob acc o u se. As a r esu lt , t he rati on ale a nd m o ti v ati on f o r qu itti ng t ob acc o u se li k ely d i f f e r s a m ong cance r p atie n ts , bu t t h ere is a c on siste n t t h eme th at

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Smoking Cessation Guidelines

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e x ists . ( 1) A ll pa ti en t s shou l d b e as k e d a bou t t ob acc o u se wit h str u ct u re d assessme n t s ; ( 2 ) a ll pa ti en t s who u se t ob acc o o r are at ris k f o r rela p se s hou l d b e o f f e r ed ev i dence - b ase d cessati on s uppo rt; a nd 3 ) t ob acc o assessme n t and cessa ti on suppo rt s hou l d o cc u r at t h e time o f d ia gno sis , dur i ng t rea tm en t , and du ri ng f o ll o w- up f o r all ca n cer p atie n ts . E m p iri c tr ea tm en t o f t obac c o u se by ca n cer p atie n ts is f und ame n tall y s uppor t ed by P ub li c Hea lt h Ser v ice (PHS) G u i d eli n es t h at are b ase d on e v i d e n ce fr o m t obacco cessa t ion e f f o rts i n non ca n cer p atie n ts . Ori g i n all y iss u e d i n 1996 and r enewed i n 2008, T h e Cli n ic a l Pr a ctice G u i d eli n e: T r e a ti ng T obacco Use and Dep e nd e n ce is a PHS-s pon s o re d, e v i d e n ce- b a sed gu i d eli ne des i gned t o ass i s t h ealt h -care p r ov i d ers i n d eli v eri ng a nd s uppor ti ng e f f ec ti ve s m ok i ng cessati on treatme n t . , T h e b asic r ec o mm enda ti on s t a t es t ha t c l in icia n s s hou l d c on siste n tl y i d e n tif y , do c u me n t , and tr ea t eve r y t ob acc o u ser see n i n a h ealt h -care setti ng. Deta ils of cessa t i on suppo rt r ange fr o m b rief t o i n te n si v e i n ter v e n ti on, bu t em ph asi ze t ha t cons i s t en t r ep eate d cessati on s uppo rt a nd e v e n b rief c oun seli ng a r e e f f ec ti ve m e t hod s t o assist p atie n ts wit h st opp i ng t ob acc o u se . I t is im po rt an t t o no t e t ha t phy sicia n - d eli v ere d i n ter v e n ti on s si gn i f ic an tl y i nc r ease l ong -t e rm a b sti n e n ce rates . I n cl ud e d are n ewer e f f ecti ve m ed i ca ti on op ti ons and str ong s uppo rt f o r c oun seli ng a nd t h e use of qu it li nes as e f f ec ti ve i n t e r v e n ti on strate g ies . As d escri b e d i n t h e PHS Gu i d eli nes, t he p ri nc i pa l s t ep s i n c ondu cti ng effecti v e sm ok i ng cessati on i n te rv e n ti ons a r e r e f e rr ed t o a s T h e 5 A ’ s: 1. A sk abou t t obacco use f or e v er y p atie n t . 2. Ad vi se eve r y t obacco user t o qu it . 3. A sse ss t he w illi ngness o f p atie n ts t o qu it . 4. A ssi s t pa ti en t s w it h qu itti ng t h r ough c oun seli ng a nd ph armac o t h era p y . 5. A rr ange f o ll ow - up cessa ti on s uppo rt , p refera b l y wit h i n t h e first wee k a f te r t he qu it da t e. Th e r e i s a s tr ong ev i dence b ase f o r t h ese i n ter v e n ti on s as do c u me n te d in t h e cli n i ca l p r ac ti ce gu i de li ne .

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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An al go rit h m i s p r ov i ded t o gu i d e cli n icia n s i n im p leme n ti ng t h e fi v e A ’ s i n t o cli n i ca l cance r ca r e ( ) I n cl ud e d i n t h e al go rit h m ar e s ugg est ed ques ti ons t ha t a r e u sef u l t o acc u ratel y assess t ob acc o u se by ca n ce r p ati en t s whe r e pa ti en t s ca n g e n erall y b e d i v i d e d i n t o c u r r e n t , f o r mer , or n ever s m oke r s. T he fir s t s te p ( A S K ) is t o i nqu ire a bou t a nd do c u me n t t ob acc o u se behav i o r s f o r eve r y p atie n t at e v er y v isit i n cl ud i ng f o ll o w- up v isits . W he r eas a m o r e co m p re h e n si v e e v al u ati on is n ecessar y at t h e firs t c on s u lt , on l y upda t es t o cu rr en t t ob acc o u se are n ee d e d at f o ll o w- up. In cl ud i ng s m ok i ng s t a t us asse ssme n ts as a “ v ital si gn ” f o r all p atie n ts si gn i f ic an tl y i nc r eases t he i den tificati on a nd treatme n t f o r p atie n ts .

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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T ob acc o - use s t a t us s ti cke r s on p a p er c h arts o r a n a u t o mate d remi nd er s y stem f or e l ec tr on i c r eco r ds ca n i n crease c o m p lia n ce wit h t ob acc o assessme n t s W it h t he r ecent Mea n i ng f u l Use sta nd ar d s t h at were im p lem en t ed i n 20 1 1, hosp it al s u si ng a n electr on ic me d ical rec o r d (EMR) a r e esse n ti a ll y r equ ir ed t o docu me n t t ob acc o u se A rece n t re po rt u tili zed t h e E M R t o im p l e m en t m and at o r y t ob acc o assessme n ts i n ca n cer p atie n t s d em on st ra ti ng t ha t j us t a f ew qu esti on s at t h e i n itial e v al u ati on a nd at fo ll ow-up cou l d y i e l d h i gh r ef erral . Less t h a n 1 % o f referrals were d elay ed wh e n as sess m en t s we r e r epea te d on a m on t h l y b asis rat h er t h a n at e v er y cli n ic v isit . T hese fi nd i ngs r edu ce t h e cli n ical bu r d e n a nd p atie n t fati g u e ass o ciate d w it h r epea t ed asses sme n ts as fre qu e n tl y as e v er y d a y s u c h as in p atie n ts w ho a r e tr ea t ed w it h d ail y R T o r C T . A t t he tim e o f t h i s chap t e r release , t h ere were no n ati on al gu i d eli n es f o r im p lem en t a ti on o f spec ifi c qu esti on s t o assess t ob acc o u se i n ca n cer p atie n ts . Howeve r , p r ov i d es e f fecti v e qu esti on s f o r assessi ng t ob acc o u se i n cance r pa ti en t s b ase d on a dv ice fr o m pub lis h e d r e por ts , Cu rr en t , f o rm e r , a nd n e v er sm ok ers are i d e n tifie d i n a st ru ct ured m anne r . P a ti en t s who u se t ob acc o wit h i n t h e p ast 30 d a y s s hould h a v e st ruc t u r ed suppo rt t o qu it t ob acc o u se , mai n tai n a b sti n e n ce , a nd

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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pr e v e n t r e l apse. A lt hough no t e xp licitl y state d by a ny s p ecific gu i d eli n e s, as k i ng a bou t t obacco use i n famil y mem b ers o f ca n cer p atie n ts ma y b e im por ta n t because f a mil y m e m b ers o fte n s uppo rt ca n cer p atie n ts du ri ng a nd fo ll ow i ng tr ea tm en t , bu t con ti nu e d sm ok i ng by famil y mem b ers ca n ma ke qu itti ng much m o r e d i f fi cu lt Ad vi s i ng i s t he second s t ep i n p r o m o ti ng e f fecti v e t ob acc o cessati on t hat i nvo l v es g i v i ng c l ea r , s tr ong, and p ers on alize d a dv ice t o st op t ob acc o u s e. Th is a dv i ce shou l d i nc l ude t he im po rta n ce o f qu itti ng sm ok i ng, s u c h as e xp licit i n f o rm a ti on on t he ri sk s o f c on ti nu e d sm ok i ng a nd t h e b e n efits o f cessati on f o r cance r tr ea tm en t ou tc o mes a nd ov erall h ealt h re g ar d less o f ca n ce r diagnos i s. T h i s i nc l ud es a d isc u ssi on o f ho w it is no t “t oo late” t o qu it a nd t ha t qu itti ng w ill i n fact b e n efit t h eir ca n cer treatme n t e f ficac y a nd ca n ce r ou t co m e . P a ti en t s can als o c on si d er t h e c o st sa v i ng s o f st opp i ng a sm ok i ng hab it . C li n i c i ans m us t b e p artic u larl y se n siti v e t o a vo i d c on t r i but i ng t o any pe r ce i ved b lame f o r t h e p atie n t ’ s ill n ess .

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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Cli n ician s m us t r e m e m be r t h at m o st p atie n ts starte d sm ok i ng i n a do lesc ence and d i d no t co m p letel y und ersta nd t h e ris k s ass o ciate d wit h t ob acc o u se. A t t he sa m e time , t h e se v ere a dd icti on ass o ciate d wit h c h r onic t ob acc o u se m akes it d i f fi cu lt t o st op. Th e nex t s t ep i s assess i ng d e p e nd e n ce a nd willi ngn ess t o qu it . As k i n g “ How s oon a ft e r wak i ng do you sm ok e you r first ci g arette?” assesses n ic o ti n e dependence, w it h h i gh d e p e nd e n ce ass o ciate d wit h a s ho rter i n te rv al be t ween wak i ng and th e first ci g arette . Nic o ti n e d e p e nd e n ce i s pr e d icti ve o f s m ok i ng cessa ti on ou tc o mes a nd ca n b e u se d as a good i nd icat o r o f t he i n t ens it y o f c essati on treatme n t n ee d e d, s u c h as t h e n ee d f o r ph a r ma co t he r ap y De t e r m i n i ng t h e p atie n t ’ s m o ti v ati on a nd i n terest in qu itti ng ar e c riti ca l pa r a m e t e rs t h at i n fl u e n ce t h e t yp es o f i n ter v e n ti on st r ate g ie s t o be e m p l oyed. D i f fere n t strate g ies f o r qu itti ng are b ase d on t he t r a n st h eor e ti ca l m ode l o f chang e a nd m o ti v ati on al i n ter v iewi ng sta n ce , wh ic h recogn i zes t ha t un i que i n ter v e n ti on messa g es a nd strate g ies are n ee d e d to op tim a ll y p r o m o t e sm ok i ng cessati on b ase d on a p atie n t ’ s r ea d i n es s t o qu it s m ok i ng . I n t h e g e n eral popu lati on, rec o mme nd ati ons e n c our ag e t ha t c li n i c i ans se t a tar g et qu it d ate wit h i n 30 d a y s . H o we v e r , f o r

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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ca n ce r p ati en t s, t he r eade r i s e n c ou ra g e d t o c on si d er a n u r g e n t n ee d t o st op sm ok i ng imm ed i a t e l y . If pa ti en ts are un a b le t o qu it imme d iatel y , t h e n p atie n ts s hou l d be encou r age d t o imme d iatel y re du ce t ob acc o u se a nd t o set a qu it da t e as soon as poss i b le b ase d on t h e t yp ical n ee d t o start ca n cer t r eatme n t i n t he imm ed i a t e f utu re . A ssisti ng pa ti en t s w it h s m ok i ng cessati on i nvo l v es cli n icia n s h el p i ng the p atie n t des i gn and im p l e m en t a s p ecific qu it p la n o r b r o a d l y e nh a n ci ng t he m o ti v ati on t o qu it t obacco. Pr o m o ti ng a n effecti v e qu it strate gy f o r ca n cer p atie n ts s hou l d cons i s t o f ( 1 ) setti ng a qu it d ate (imme d iatel y o r as s oon a s po ssi b le) , ( 2 ) r e m ov i ng a ll t ob acc o -relate d p r odu cts fr o m t h e e nv ir on me nt ( e .g., ci ga r e tt es, ash tr ays, li gh ters) , ( 3 ) re qu esti ng s uppo rt fr o m famil y an d fr ie nd s , ( 4 ) d i scuss i ng cha ll eng es t o qu itti ng, a nd ( 5 ) d isc u ssi ng o r pr esc r i b i ng pha rm aco t he r apy wh ere a pp r op riate . Patie n ts s hou l d als o b e prov i d e d i n f o rm a ti on on cess ati on s uppo rt ser v ices ( . I n t h e ca n ce r s e tti ng, pa ti en t s can a l so b e i n f o rme d t h at sm ok i ng cessati on is a c r itical co m ponen t o f cance r c are ov er w h ic h t h e y h a v e c o m p lete c on tr ol, t h e r e by con f e rri ng so m e pe r s o n al c on tr o l ov er t h eir ca n cer care . Patie n t s who a r e unw illi ng t o qu it s hou l d c on ti nu e t o recei v e re p eate d assessme n t s and counse li ng to h el p m o ti v ate p atie n ts t o qu it sm ok i ng. Th ese pa ti en t s shou l d be encou ra g e d t o ma k e imme d iate re du cti on s i n t ob acc o u se and wo r k t owa r d a b sti n e n ce as s oon as po ssi b le . Cli n icia n e du cati o n , r eassu r ance, and gen tle e n c ou ra g eme n t ca n h el p t h em t o c on si d e r chang i ng t he ir s m ok i ng b e h a v i o rs . S p ecific strate g ies i n cl ud e d isc u ssin g t he pe r sona l r e l evan ce o f sm ok i ng a nd b e n efits t o cessati on, prov i d i n g suppo rt and acknow le dg i ng t h e d i f fic u lt y o f qu itti ng, e du cati n g p atie n ts a bou t t he pos iti ve co nse qu e n ces o f qu itti ng sm ok i ng, a nd d isc u ssin g ava il ab l e pha rm ac ol og ic met hod s t o assist wit h qu itti ng . T he em ph asi s shou l d be p l aced on p atie n t a u t ono m y t o qu it . M o ti v ati on al st r ate g ie s f o r pa ti en t s unw illi ng t o qu it ca n b e em p l oy e d (e .g., as k i ng open -e nd e d ques ti ons, p r ov i d i ng a f firmati on s , reflecti v e liste n i ng,

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Implementing Smoking Cessation Into Clinical Practice

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r e qu i r es a conce rt ed e f f o rt , ma y re qu ire re p eate d attem p ts , a nd s y m p t o m s w ill no t r eso l ve imm ed i a t e l y . Cli n icia n s s hou l d c oun sel p atie n ts on a r e p eate d bas i s, r ecogn i ze suc cess , a nd p r ov i d e re p eate d assista n ce if p atie n ts re l apse.

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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Pharmacologic T r eatment for Smoking Cessation

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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Th e pr i nc i p l es o f pha rm aco t h era py t o h el p p atie n ts qu it sm ok i ng are fund am en t a ll y based on r edu ci ng t h e cra v i ng ass o ciate d wit h n ic o ti n e w it hdr a wa l . N i co ti ne r ep l acem e n t t h era py (N R T) , i n t h e f o rm o f p atc h es , l o ze ng es , i nha l e r s, sp r ays, and gu m , v are n icli n e (C h a n ti x ) , a nd bup r op i on (Zyb a n) a r e t he t h r ee p ri nc i pa l first-li n e ph armac o t h era p ies rec o mme nded

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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B uprop i on i nh i b it s t he r eup t a ke o f bo t h dop ami n e a nd no re p i n e ph ri n e , t h e r e by i nc r eas i ng dopa mi ne a nd no re p i n e ph ri n e c on ce n trati on s i n t h e mes o li mb i c sys t e m s Buprop i on als o a n ta gon izes t h e n AC h R , t h ere by l ow e r i n g t he r ewa r d i ng e f f ec ts o f n ic o ti n e S hou l d a n a b sti n e n t sm ok e r r ela p se , bup r op i on m ay f unc t ion t o re du ce t h e p leas u re o f ci g arette sm oking e xp e r ien ced by t he s m oke r a nd h el p t o p re v e n t f u rt h er rela p se . A meta-a n al y sis f ound t ha t s m oke r s w ho recei v e d bup r op i on were twice as li k el y as t ho se w h o r ece i ved p l acebo t o h a v e ac h ie v e d l ong -term a b sti n e n ce at eit he r a 6- or 12 -m on t h f o ll ow - up . V a r e n i c li ne ( Chan ti x ) i s a α 4 β 2 n AC h R p artial a gon ist t h at p r odu ces s u stai n e d dopa mi ne r e l ease in t h e mes o lim b ic s y stem t h at recei v e d FDA a pprov a l f o r tr ea ti ng t obacco d e p e nd e n ce i n 2006. S u stai n e d dop ami n e r elease m a i n t a i ns a no rm a l sy stemic le v el o f t h e n e u r o tra n smitte r , w h ic h h el p s t o reduce c r av i ng and w it hd rawal du ri ng a b sti n e n ce . V are n icli n e als o a n t agon i zes t he r ewa r d i ng e f fects o f n ic o ti n e . Beca u se v are n icli n e atte nu at es t he p l easu r e s m oke rs e xp erie n ce fr o m sm ok i ng, it ma y d ecrea se m o ti v ati on t o s m oke and p r o tect t h em fr o m rela p se . O n e o f t h e i n itiall y r e por te d r ando mi zed c li n i ca l trials t h at c o m p are d v are n icli n e ( 2 m g ) , buprop i on ( 300 m g ) , and p l acebo s ho we d t h at v are n icli n e was s up eri o r t o buprop i on and p l acebo, w it h ov erall c on ti nuou s a b sti n e n ce rates b etwee n 10% t o 23 % . A m e t a - ana l y sis d em on strate d t h at t h e 1 -m g d ail y do se a pprox im a t e l y doub l ed, whe r e as t h e 2 -m g d ail y do se a pp r ox imatel y tri pled t h e li k eli hood o f l ong -t e rm a bsti n e n ce at 6 m on t h s as c o m p are d t o p lace bo . As a r esu lt , t he 1 -m g d ail y do se ca n b e c on si d ere d as a n alte rn ati ve shou l d t he pa ti en t e xp erie n ce si gn ifica n t do se-relate d si d e e f f ects . S eve r a l m e t a - ana l yses h a v e s ho w n t h at v are n icli n e is s up eri o r t o buprop i on and p l acebo i n t he ge n eral popu lati on

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

nan nan

In J u l y 2009, t he F DA i ss ue d a war n i ng after re po rts t h at s o me p atie nts attem p ti ng t o qu it s m ok i ng wh ile u si ng v are n icli n e o r bup r op i on e xp e r ien ced unusua l changes i n b e h a v i o r , d e p resse d m ood, w o rse n i ng o f d e pr essi on, o r had t hough t s o f s u ici d e . T h is h as p r o m p te d rec o mme nd at ions t h at h ea l t h - ca r e p r ov i de r s e li ci t i n f o rmati on a bou t a p atie n t ’ s p s y c h iatric h ist ory p ri o r t o p r esc ri b i ng va re n icli n e o r bup r op i on t o cl o sel y m on it o r c h a ng es i n m ood and behav i or du ri ng t h e c ou rse o f treatme n t . H o we v e r , upd ate d r ecen t sa f e t y s t ud i es e x ami n i ng v er y lar g e d ata b ases ( on e d ata base of N = 1 19,546, one da t abase o f N = 35,800 ) re g ar d i ng safet y h a v e s hown no d i f f er ence i n neu r opsych i a tric si d e e f fects b etwee n v are n icli n e o r buprop i on as co m pa r ed t o N R T a nd no i n crease d ris k o f d e p ressi on

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Pharmacologic T r eatment for Smoking Cessation

nan nan

Ano t h e r p r ospec ti ve s t udy sho we d no a dv erse e v e n ts w h e n treati ng p a r tici pan t s w it h cu rr en t o r pa st maj o r d e p ressi on a nd als o s ho we d h i ghe r a b sti n e nce r a t es f o r t he va r en icli n e g r oup as c o m p are d t o p lace bo at wee ks 9 t o 52 (20.3 % ve r sus 10.4 % , p <0.001 ) V are n icli n e s hou l d b e c on si d e red a v i ab l e cessa ti on ph armac o t h era py f o r ca n cer p atie n ts . Th e c li n i ca l p r ac ti ce gu i del i n e als o i d e n tifies tw o non - n ic o ti n e –b ase d me d icat ions—c l on i d i ne and n o rtri p t y li n e — as sec ond -li n e ph a r ma co t he r ap i es f o r t obacco d e p e nd e n ce . A sec ond -li n e a g e n t is u se d wh e n a sm oke r canno t use fir s t-li n e me d icati on s du e t o eit h er c on t r ai nd i ca ti ons o r l ack o f e f fecti v e n ess . B o t h cl on i d i n e , a n a n ti hype rt ens i ve, and no rtri p t y li n e , a tric y clic a n ti d e p ressa n t , h a v e b ee n s hown t o e f f ec ti ve l y ass i s t s m ok ers ac h ie v e a b sti n e n ce . U n f o rt un at el y , ma ny pa ti en t s who qu it w ill e ve n t u all y rela p se , a nd rates o f l ong -term a b sti n e nce r e m a i n l o w . Becaus e sm ok i ng po ses e no rm ou s h ealt h ris k s t o i nd i v i du al s and t he ir f a mili es, e v e n a m od est re du cti on i n sm ok i ng ma y t r a n slate i n t o a s i gn ifi can t im p act on pub lic h ealt h. Cli n icia n s s hou l d c on ti nue t o encou r age r eca l c itra n t sm ok ers t o st op t ob acc o u se a nd u se ph a r ma co t he r apy whe r e app r op riate wit h re p eate d qu it attem p ts .

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Empirically T ested Cessation Interventions with Cancer Patients

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Th e ov er whe lmi ng m a j o rit y o f cessati on researc h h as b ee n p erf o rme d i n the g e n e r al p opu l a ti on, bu t t he r e a re se v eral st ud ies t h at h a v e b ee n p erf o rme d i n ca n cer pa ti en t s. G rit z e t a l . c ondu cte d t h e first phy sicia n - o r d e n tist- d eli v e r ed r ando mi zed cessa tio n i n ter v e n ti on c o m p aris on i n 186 n ewl y d ia gno se d head and neck can cer p atie n ts . Patie n ts were treate d wit h eit he r mi n imal adv i ce o r an enhanced i n ter v e n ti on wit h trai n e d cli n icia n s c on sisti ng o f s tr ong pe r sona li z e d a dv ice t o st op sm ok i ng, a c on tracte d quit d ate , tai lo r ed w ritt en m a t e ri a l s, a nd boo ster a dv ice sessi on s . N o si gn ifica nt d i f f e r e nces we r e f ound be t we e n treatme n ts , bu t a 70.2 % c on ti nuou s a b sti n e nce r a t e was f ound a t 12 -m on t h f o ll o w- up re g ar d less o f treatme n t c ond iti on, sugges ti ng t ha t m any ca n cer p atie n ts ca n b e n efit fr o m b rief phy sicia n - de li ve r ed adv i ce. A later st udy by Sc hno ll et al . , c o m p ari ng c ogn iti ve behav i o r a l tr ea tm en t wit h sta nd ar d ize d h ealt h e du cati on a dv ic e, als o f aile d t o fi nd s i gn ifi can t d i f fere n ces i n qu it rates . All p atie n ts recei ved N R T , a nd qu it r a t es i n bo t h g ro up s a pp r o ac h e d 50 % at 1 -m on t h f o ll o w- up a nd 40 % a t 3 -m on t h f o ll ow - up. Add iti ona l s t ud i es, r ang i ng fr o m 15 t o 80 p atie n ts , e x ami n e d nu rse- d eli v e r ed cessa ti on i n t e r ven ti on s f o r a v ariet y o f ca n cer p atie n ts . T h e l o w est cessati on r a t es we r e f ound w it h a si ng le sessi on i n ter v e n ti on : a 21 % cessati on r a t e i n t he i n t e r ven ti on g r oup v ers u s 14 % i n t h e u s u al care g r oup 6 w ee k s’ pos ti n t e r ven ti on Hi gh er cessati on rates were ass o ciate d wit h a m or e i n te ns i ve i n t e r ven ti on con sisti ng o f t h ree i np atie n t v isits , s upp leme n t a r y m a t e ri a l s, and fi v e po st d isc h ar g e f o ll o w- up c on tacts . Add iti ona l s t ud i es de m ons tr a te h i gh er cessati on rates wit h m o re i n te n si ve i n te rv e n ti on ( 40 % t o 75 %) as c o m p are d wit h u s u al care ( 43 % t o 50 %) , s ugg esti ng m o r e i n t ens i ve i n ter v e n ti on s ma y y iel d h i gh er cessati on rates . – In g e ne r a l , m o r e i n t ense i nt er v e n ti on s a pp ear t o b e m o re efficaci ou s , b ut e v e n br i e f adv i ce i s im po rt an t t o ac h ie v e t ob acc o cessati on. In a rando mi zed tri a l o f 432 ca n cer p atie n ts c oo r d i n ate d by t h e Easter n C oop e r ati ve Onco l ogy G r oup (ECOG) wit h a phy sicia n - d eli v ere d i n te rv e n ti on ( co m p ri sed o f ces sati on a dv ice , op ti on al N R T , a nd writte n mate r ial s ) o r usua l ca r e ( uns truct u re d a dv ice fr o m phy sicia n s) , t h ere wer e no si gn ifi can t i n t e r ven ti on e f fects a nd g e n erall y l o w a b sti n e n ce rates ( 1 2%

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Empirically T ested Cessation Interventions with Cancer Patients

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t o 15% a t 6 t o 12 m on t hs ) H o we v e r , p atie n ts wit h h ea d a nd n ec k o r l ung ca n ce r we r e s i gn ifi can tl y m o r e li k el y t o h a v e qu it sm ok i ng c o m p are d t o p atie n ts wit h t u m o r s t ha t we r e no t sm ok i ng relate d. A n al y ses o f ou tc o me s fro m t he Mayo C li n i c N i co ti n e De p e nd e n ce Ce n ter f ound t h at alt hough l ung ca nce r pa ti en t s we r e m or e li k el y t o ac h ie v e 6 -m on t h t ob acc o a b sti n e nce t han con tr o l s ( 22% v ers u s 14 %) , no si gn ifica n t d iffere n ces w e r e ob se rv e d a ft e r ad j us ti ng f o r cov ariates . Garces et al . als o f ound no si gn i f ic an t d i f f e r ences i n abs t in e n ce rates b etwee n h ea d a nd n ec k ca n cer p atie n ts a nd con tr o l s ( 33 % ve rs u s 26 %) . H o we v e r , h i gh er a b sti n e n ce rat es w e r e found f o r bo t h head and n ec k a nd l ung ca n cer p atie n ts treate d wit hin 3 m on t h s o f d i agnos i s co m pa r ed t o t ho se treate d f o r m o re t h a n 3 m on t h s a fte r t h e d ia gnos i s, e m phas i z i ng t h e po te n tial im po rta n ce o f t h e te a c hab le mom e n t a t t he tim e o f t he can cer d ia gno sis . Th e po t en ti a l im po rt ance o f a dd ressi ng sm ok i ng c o m b i n e d wit h c on si d e r i ng co m o r b i d d i sease h as b ee n no te d i n a few st ud ies . I n a r a ndo mi zed head and neck can cer p atie n ts o f u s u al care v ers u s 9 t o 1 1 sessi on s o f a nu r se - ad mi n i s t er e d i n ter v e n ti on c on sisti ng o f c ogn iti v e- b e h a v i ora l t he r apy and m ed i c ati on s , tar g eti ng c o m o r b i d sm ok i ng, d ri nk i ng, a nd d e press i on s i gn ifi can tl y i n crease d qu it rates at 6 -m on t h f o ll o w- up f o r t h e i n te rven ti on g r oup co m par e d t o t h e u s u al c on tr o l g r oup ( 47 % v ers u s 31%, p < 0.05 ) I n a r ando mize d trial o f 246 ca n cer p atie n ts treate d wit h 9 w ee k s o f N R T w it h o r w it hou t bup r op i on, t h ere was no si gn ifica n t d i f f e r e nce w it h t he add iti on of bup r op i on t o N R T , bu t i n p atie n ts wit h d e pr essi ve sy m p t o m s, bup r opion i n crease d a b sti n e n ce rates , l o were d w it hdr a wa l , and im p r oved qu alit y o f life . Patie n ts wit hou t d e p ressi on s y m p t o m s d i d equa ll y we ll wh e n treate d wit h bup r op i on v ers u s tra n s d er mal n ic o ti n e and counse li ng a l one . Patie n t r ec r u itm en t has be e n a p r ob lem no te d by s o me st ud ies , i n cl uding 5.5 y ea rs t o acc r ue 246 pa ti ent s wit h tele phon e scree n i ng o f ov er 7,500 po te n tial pa ti en t s . A p il o t trial o f v are n icli n e i n t ho racic on c o l ogy p ati ents r e qu i r e d sc r een i ng 1,130 pa tie n ts t o accr u e 49 p artici p a n ts ra ndo mize d t o a 12-w eek cou r se o f e it he r va r e nicli n e o r p lace bo p aire d wit h a b e h a v i o ral c oun seli ng p l a tf o rm o f seven sessi on s . A ra ndo mize d trial o f 185

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Empirically T ested Cessation Interventions with Cancer Patients

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sm ok i ng cance r pa ti en t s co m p ari ng t h e efficac y o f a ho s p ital- b ase d sta nd a rd ca r e s m ok i ng cessa ti on m od el v ers u s sta nd ar d care a ug me n te d by a b e h a v ior a l t ape ri ng r eg im en v ia a h a ndh el d d e v ice b ef o re i np atie n t ho s p ital iza ti on f o r cance r su r g er y d em on strate d no d i f fere n ce i n qu it rate s (bo t h 32 % , ) Howeve r , over 29,000 p atie n ts were scree n e d t o c ondu ct a r a ndo mi zed c li n i ca l tri a l w it h a sm ok i ng ca n cer p atie n t popu lati on. T h es e st ud ies h i gh li gh t t he po t en ti a l d i f fic u lt y recr u iti ng p artici p a n ts w ho sm oke, i n cl ud i ng cons i de r a ti ons f o r t h e im po rta n ce o f me d ical c o m o r b i d it y i n gu i d i ng s m ok i ng cessa ti on treatme n t , p atie n t mi x (m u lti p le t u m o r sites) , t r eatme n t s t a t us ( awa iti ng tr e atme n t t o c o m p lete d treatme n t) , v ariati on i n sta g e of d i sease, and cons i de ri ng ho w p s y c h iatric c ond iti on s s u c h as d e pr essi on r e fl ec t t he d i f fi cu l ty o f c ondu cti ng researc h i n t h e on c o l ogy setti ng an d t he im po rt ance o f t h ese v aria b les i n f u t u re st ud ies . A lt hough acc r u i ng pa ti en ts t o i n ter v e n ti on trials ma y seem d isc ou ra g i ng, se v e r al s t ud i es de m ons tr a t e t h e b e n efit o f c oun seli ng ov er self- h el p. E mm on s e t a l . conduc t ed a r a ndo mize d c on tr o lle d trial i n 796 young a du lt s urv i vo r s o f ped i a tri c can cer t h at i n cl ud e d si x calls , tail o re d a nd ta r g ete d w ritt en m a t e ri a l s, and op ti on al N R T as c o m p are d wit h self- h el p . Si gn i f ica n tl y h i ghe r qu it r a t es were f ound i n t h e c oun seli ng g r oup c o m p a red t o t he se lf- he l p g r oup at all re po rte d f o ll o w- up time po i n ts , i n cl ud i ng 12 m on t hs ( 15 % ver s u s 9 %; p <0.01 ) . A ra ndo mize d trial o f a m o ti v ati ona l i n t e r v i ew i ng - ba se d sm ok i ng cessati on i n ter v e n ti on i n a s outh Au st r ali an hosp it a l was de li v ere d ov er a 3 -m on t h p eri od, c on siste d o f m u lti p le con t ac t s w it h a tr a i n e d c oun sel o r , a nd p r ov i d e d s upp leme n tar y mate r ial t a il o r ed t o cance r pa t i e n ts wit h N R T T h e c on tr o l g r oup recei ved br ie f a dv i ce t o qu it and gene ric s upp leme n tar y material . Q u it rates d i d not d i f f e r by tr ea tm en t g r oup ( 5% t o 6 % at 3 -m on t h f o ll o w- up ) , bu t t h e i n te rv e n ti on g r oup was s i gn ifica n tl y m o re li k el y t o re po rt attem p ts t o qu i t sm ok i ng.

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Cur r ent T obacco Assessment and Cessation Support by Oncologists

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Cur r ent T obacco Assessment and Cessation Support by Oncologists

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Cur r ent T obacco Assessment and Cessation Support by Oncologists

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A ccess to cessa ti on suppo rt i s critical t o a dd ress t ob acc o u se by ca n cer p atie n ts . A r ecen t su r vey o f 58 NCI- d esi gn ate d ca n cer ce n ters i nd icate d t hat a bou t 80 % r epo rt ed a t obacco u se p r og ram a v aila b le t o t h eir p atie n ts a nd a bou t 60 % r ou ti ne l y o f f e r ed e du cati on al materials , bu t less t h a n 50 % h a d a d esi gn at ed i nd i v i dua l who p ro v i d e d ser v ices . A rece n t s u r v e y o f ov er 1,500 m e m be r s o f t he I n t e r na ti on al Ass o ciati on f o r t h e St udy o f L ung Ca n ce r (I A SL C and a pa r a llel st udy o f 1,197 ASCO mem b er s

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Cur r ent T obacco Assessment and Cessation Support by Oncologists

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Cur r ent T obacco Assessment and Cessation Support by Oncologists

nan nan

ob se rv e d t ha t app r ox im a t e l y 90 % o f phy sicia n s b elie v e t h at t ob acc o a f f ects ou tc o m es, t obacco cessa ti on shou l d b e a sta nd ar d p art o f ca n cer care , a nd a pprox im a t e l y 80 % r egu l a rl y a dv ise p atie n ts t o st op u si ng t ob acc o, bu t only a pprox im a t e l y 40 % d i scuss m e d icati on s o r assist wit h qu itti ng. D o mi n a nt p e r cei v e d ba rri e r s t o cessa ti on s uppo rt were p atie n t resista n ce t o treatme nt, a n i n a b ilit y t o ge t pa ti en t s t o qu it , a lac k o f cessati on res ou rces , a nd a lac k of cli n ici an educa ti on. T hese d ata s ho we d t h at e v e n m o ti v ate d cli n icia n s a r e no t r e gu l a rl y p r ov i d i ng t obacco cessati on s uppo rt . A rece n t s u r v e y o f 155 acti v el y acc r u i ng coope r a ti ve g r oup cli n ical trials f u rt h er d em on strate d th at on l y 29 % o f ac ti ve tri a l s co llecte d a ny t ob acc o u se i n f o rmati on, 4.5 % c o llecte d any t obacco use i n f o rmati on at f o ll o w- up, a nd non e a dd resse d t ob acc o c essa ti on . F ew onco l ogy meeti ng s o f fer e du cati on al w o r k s hops o r tal k s , a nd t hey a r e o ft en poo rl y atte nd e d w h e n t h e y are o ffere d.

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Cur r ent T obacco Assessment and Cessation Support by Oncologists

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ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Examples of Model T obacco T r eatment P r ograms

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Se v e r al ded i ca t ed t obacco tr ea tme n t p r og rams at ca n cer ce n ters h a v e b e en d e v el op e d. con tr a sts t h e c o re eleme n ts o f f ou r acti v e m od el progr ams a t t he end o f 2013 (U n i v ersit y o f T e x as M . D . A nd ers on Ca n cer Ce n te r , Roswe ll P a r k Cance r I n stit u te , Y ale Ca n cer Ce n te r , a nd Mem o ri al Sl o a n Ke tt e ri ng Cance r Cen ter) , eac h o f w h ic h em p l oy d iffere n t met hod s to h el p ca n c e r pa ti en t s qu it s m ok i ng. All p r og rams f o ll o w t h e e v i d e n ce- b a sed 5 A ’ s mo de l desc ri bed p r ev i ou sl y fr o m PHS G u i d eli n es All p r og rams w e r e m ade ava il ab l e t o pa ti ent s at t h eir res p ecti v e me d ical ce n ters a nd a re now d esi gned t o eva l ua t e and treat all p atie n ts w ho self-re po rt c u rre n t t ob acc o u se. Im po rt an tl y , no t all ca n cer ce n ters ca n treat sm ok i ng cessat ion i n t h e sam e m anne r . Fi nanc i ng o f a cessati on p r og ram is critical a nd ma y

ADDRESSING T OBACCO USE BY THE CANCER PA TI E NT

Examples of Model T obacco T r eatment P r ograms

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i n cl ud e i ns tit u ti ona l f unds, s t a te f und s , researc h f und s , a nd t h ir d - p art y b illi ng. N o t ab l y , g i ven t he b r o a d s p ectr u m o f a dv erse h ealt h e f fects ass o ciate d w it h s m ok i ng, canc er ce n ters s hou l d caref u ll y c on si d er t h e po te n tial hea lt h bene fit s and c o st sa v i ng s ass o ciate d wit h t ob acc o cessati on du e t o reduc ti ons i n tr ea tm en t c o m p licati on s a nd rec u rre n ce ass o ciate d with sm ok i ng by cance r pa ti en t s. T h ere is no on e “c o rrect” wa y t o create a nd s u stai n a t obacco tr ea tm en t p ro g ram at a ca n cer ce n te r , bu t at t h e v er y lea st a nd c on si s t en t w it h ev i dence, ri go r ou s b e h a v i o ral c oun seli ng s hou l d b e prov i d e d and, if poss i b l e, m ed icati on ma n a g eme n t as well .

FUTURE CONSIDER A TI O NS

Resea r ch Considerations

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Resea r ch Considerations

FUTURE CONSIDER A TI O NS

Resea r ch Considerations

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FUTURE CONSIDER A TI O NS

Resea r ch Considerations

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A lt hough s m ok i ng i s t he p re do mi n a n t f o rm o f t ob acc o c on s u m p ti on, all t ob a cco p r oduc t s shou l d b e c on si d ere d. A f u rt h er und ersta nd i ng o f t he e f f ec ts o f t obacco on t he e f ficac y a nd t ox icit y o f ca n cer treatme n t , t umo r r es ponse, qua lit y o f lif e, s ur v i v al , rec u rre n ce , c o m p lia n ce , sec ond

FUTURE CONSIDER A TI O NS

Resea r ch Considerations

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pr imar y , and noncance r -r e late d c o m o r b i d it y is n ee d e d. All ca n cer d isea se s it es and s t ages a re im po rta n t t o c on si d e r . 2. Unders t and i ng t he e ff ec t s o f t oba cc o and cess a ti on on c an cer b i o l og y . A lt hough no t a p rim a r y f o c u s o f t h is c h a p te r , t ob acc o a nd t ob acc o - r elat ed p r oduc t s i nc r ease tum o r g r o wt h, a ng i og e n esis , mi g rati on, i nv a s i on and m e t as t as i s and d ecrease res pon se t o c onv e n ti on al ca n ce r t r eatm en t s such as C T and R T . T h ese a nd o t h er areas are im po rta n t t o c on si de r , i nc l ud i ng t he po te n tial e f fects on imm un e-relate d t h era py a nd v acci ne deve l op m en t . I n vi v o m od els o f e xpo s u re a nd ca n cer res ponse a r e no t we ll deve l oped, ye t are critical t o t h is researc h area . W o r k is also n ee d e d t o assess t he e f f ec t o f eme r g i ng t ob acc o -relate d p r odu cts s u c h as e - ci ga r e tt es. 3. Ad v ance unders t and i ng o f m od els t o i n c r e a se a ccess t o cess a ti on s upp o r t and i nc r ease e ffi ca cy o f t oba cc o cess a ti on met hod s f o r c an c er pa tie n t s. T h i s d i ve r se a r ea i n cl ud es assessi ng t h e timi ng o f i n ter v e n ti on, i n te ns it y , du r a ti on, f o ll ow - up, a nd t h e po te n tial e f fects o f h arm- r e duc ti on s tr a t eg i es. Cessa ti on ph armac o l ogy re qu ires a dd iti on al c on si de r a ti on i n co m b i na ti on wit h un i qu e a pp r o ac h es t o m o ti v ati on a l a nd behav i o r a l counse li ng i n ca n cer p atie n ts . Si gn ifica n t w o r k is n ee ded t o d i sse mi na t e ev i dence - ba se d cessati on s uppo rt a nd t o assess t h e c ost -e f f ec t i veness o f d i f f e r en t cessati on strate g ies , p artic u larl y wit h re g ar d to im prov i ng t he cos t o f canc er care as a w ho le . Pre v e n ti ng rela p se a nd e v al ua ti ng t he sa f e t y o f tra n siti on t o alter n ati v e p r odu cts s u c h as e-ci g a re tt es i s equa ll y im po rta n t a nd i n creasi ng l y c o m p le x wit h t h e a dd iti on o f new t obacco -relate d p r odu cts . I d e n tif y i ng a nd a dd ressi ng b a rr ier s t o e f f ec ti ve cessa t ion s uppo rt is als o n ee d e d. As relate d t o t h e ca n c e r pa ti en t , c li n i c i ans and cessati on s p ecialists s hou l d c on si d er how t h ei r r esea r ch r e l a t es t o can cer care . T a k i ng a dv a n ta g e o f n ew i n te g r ated me d i ca l m anage m en t sys tems p rese n ts a si gn ifica n t oppo rt un it y t o im prove cessa ti on suppo rt access as well as t o d e v el op a m o re e f fect ive t r ac k i ng o f pa ti en t ou t com es .

FUTURE CONSIDER A TI O NS

Policy Implications and Systematic Issues

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Se v e r al na ti ona l and i n t e r na ti on al o r g a n izati on s h a v e em ph asize d t h e im por ta nce o f t obacco assessm e n ts a nd cessati on f o r t h e g e n eral popu lati on a nd for c ance r pa ti en t s t ha t i n cl ud e t oo ls t o e v al u ate t ob acc o u se at d ia gno sis , du ri ng tr ea tm en t , and f o ll o w- up a ppo i n tme n ts , as well as r ou ti ne s uppor t f o r s m ok i ng cessa ti on , – I n 2012, ASCO , wit h t h e c on t r i but i on o f t he A m e ri can Le g ac y F ound ati on, pub lis h e d a T ob acc o Cessati on T oo l k it f o r t he onco l ogy setti ng T h is e v i d e n ce- b ase d gu i d el ine i n te nd s to he l p onco l ogy p r ov i d ers i n te g rate t ob acc o cessati on strate g ies i n t o t h eir pa ti en t ca r e. U tili za ti on o f t h e EMR a nd sta nd ar d ize d, a u t o mat ed s y stems f o r m o r e e f fi cac i ous and e f ficie n t access t o t ob acc o cessati on s uppor t has a l so been sugges te d , bu t re qu ires p artici p ati on by cli n icia ns, i n stit u ti ons, i nsu r e r s, and heal t h d e p artme n ts . N o t on l y s hou l d p r ov i d ers be a w a r e of t he need f o r t obacco cessati on a nd a v aila b le i n ter v e n ti on s , bu t h ealt h- car e i ns tit u ti ons m us t als o bu il d s u c h treatme n t i n t o t h eir ov erall s y stem o f ca r e. T hus, t he i den tificati on o f p atie n ts w ho sm ok e o r u se a ny alte rn ati ve t obacco p r oduc t , referral o r d irect treatme n t by p r ov i d ers , b ill ing a nd r eim bu r se m en t f o r tr ea tme n t p r ov i d e d, a nd c on siste n t eff o rts fr o m prof essio na l onco l ogy o r gan izati on s are criticall y im po rta n t T h e t r eme ndous pub li c hea lt h bu r d e n fr o m t ob acc o -relate d d isa b ilit y a nd d ea th h as no t been coun t e r ed by a p r opo rti on al le v el o f f und i ng i n t ob acc o c on t ro l , c ance r tr ea tm en t r esea rc h, o r pub lic a dvo cac y . Researc h ers , cli n ician s, and advoca t es m ust c o me t og et h er t o p ers u a d e po lic y ma k ers to i n c r ease f und i ng i n t obacco -r e late d researc h, treatme n t , a nd po lic y i n itiati v e s on beha lf o f hea lt hy i nd i v i du als a nd p atie n ts . A un ite d fr on t i s c r iticall y needed i n suppo rt o f a c o mm on a g e nd a t h at i n cl ud es bo t h i n c r ease d t obacco - con tr o l e f f o rts a nd a dd iti on al f und i ng f o r d isease-rela ted r esea r c h and tr ea tm en t . W it h cli n ical rati on ale , gu i d eli n es , a nd a dvo cac y in p lace , t h e fi na l s t eps i n e f f ec ti v e t ob acc o c on tr o l a nd im p r ov i ng h ealt h ou tc o m es a r e t o im p l e m en t t h ese rec o mme nd ati on s i n t o p ractice .

IN T RODUCTION

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Si n ce t he he rit ab l e co m ponen t o f s o me ca n cer p re d is po siti on s h as b ee n li nk e d t o m u t a ti ons i n spec ific g e n es , cli n ical i n ter v e n ti on s h a v e b ee n for m u la ted f o r m u t a ti on ca rriers wit h i n affecte d families . T h e p rimar y i n te rv e n ti ons f o r m u t a ti on ca rriers f o r h i gh l y p e n etra n t s ynd r o mes , s u c h as m u lti p le endoc ri ne neop l as i a (MEN) , familial a d e no mat ou s po l ypo sis ( F A P ), he r ed it a r y nonpo l yposi s c o l o rectal ca n cer (CRC) , a nd h ere d itar y br east a nd ova ri an cance r synd r o mes , are p rimaril y s u r g ical . T h is c h a p ter is d i v i d e d i n t o fi ve sec ti ons addr essi ng b reast (S . G . A . G . ) , g astric (J . N . ) , ov a r ia n and endo m e tri a l ( A.B. ) , a nd MENs (J . F . M . ) a nd c o l o rectal (J . G .G., V . W .H.). F o r each, t he c li n i ca l a nd g e n etic i nd icati on s a nd timi ng o f prophy l ac ti c su r ge r y and it s e f ficac y , w h e n kno w n, are p r ov i d e d. P rop h y l ac ti c su r ge r y i n he re d itar y ca n cer is a c o m p le x p r o cess , re qu ir ing a clea r unde r s t and i ng o f t he n at u ral h ist o r y o f t h e d isease a nd v aria n ce o f p e n et r an ce, a r ea li s ti c app r ec iati on o f t h e po te n tial b e n efit a nd c on se qu e nce of a r is k -r educ i ng p r ocedu r e i n a n o t h erwise po te n tiall y h ealt hy i nd i v i dual, a nd t h e long -t e rm seque l ae o f s u c h s u r g ical i n ter v e n ti on, as well as t h e i nd i v i du al pa ti en t ’ s and f a mil y ’ s p erce p ti on o f s u r g ical ris k a nd a n tici p at ed b e n e f it .

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

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PA TIENTS A T H IGH RISK F OR BR E AST CANCER

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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Identification of Patients at Risk

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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H ist or ic a ll y , gene ti c counse li ng a nd testi ng were o f fere d by h ealt h -care prov i d e r s . Howeve r , w it h t he adv e n t o f d irect-t o -c on s u mer mar k eti ng, i nd i v i du al s m ay ob t a i n t es t s and recei v e res u lts d irectl y fr o m a c o m p a n y . Th e A m e ri can S oc i e t y o f C linical O n c o l ogy still e ndo rses p re- a nd po stt est c oun seli ng f o r t ho r ough d i sc l o s u re o f t h e im p act o f testi ng. Bef o re a ny wo ma n c ons i de r s ri sk -r educ ti on s u r g er y s u c h as b ilateral mastect o m y o r sal p i ngo-oopho r ec t o m y , r e f e r r al t o a h i gh -ris k o r g e n etic scree n i ng p r og r am is d esi r a b l e, as wo m en o ft en ov erestimate t h eir act u al b reast ca n cer ris k . Th e m os t co mm on cance r s ynd r o mes t h at p lace w o me n at ris k f o r b r east ca n ce r ar e BR C A and BR C A 2 g e n e m u tati on s . Ot h er less c o mm on s yndro m es a r e li s t ed i n

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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F o ll ow i ng r e f e rr a l f o r gene tic assessme n t , t h ree g r oup s o f p atie n ts eme r g e T he fir s t cons i s t s o f t ho se w o me n w ho h a v e und e r gon e g e n etic testi ng an d have been f ound t o h ar bo r a m u tate d g e n e ass o ciate d wit h h ig h p e n et r an ce f o r b r eas t cance r . Gi v e n t h at t h e po ssi b ilit y o f d e v el op i ng b re ast ca n ce r i n t h i s g r oup m ay be a s h i gh as 90 % , t h ere is a r o le f o r e nh a n ce d s urv eill ance o r ri sk -r educ ti on s u r g er y . T h e America n Ca n cer S o ciet y h a s pub lis h e d gu i de li nes f o r m agn etic res on a n ce ima g i ng (MRI) scree n i ng as a met hod f o r enhanced su r ve illa n ce . W o me n i n t h is first g r oup qu alif y f o r s u c h sc reen i ng, wh i ch can be o f fere d a nnu all y bu t sc h e du le d at 6 -m on t h i n te rv al s w it h sc r een i ng m a m mog ra phy t o i n crease t h e rate o f i d e n tif y i n g i n te rv al cance r s. A lt e r na ti ve l y , sim u lta n e ou s scree n i ng wit h MRI a nd mamm og r aphy t o co m pa r e on e m od alit y wit h t h e o t h er on a n a nnu al b as is ma y als o be o f f e r ed. Ano t he r c ho ice f o r t h is g r oup o f w o me n is t o pu rs ue b ilate r al ri sk -r educ ti on m as t ec t o m y wit h a n op ti on f o r imme d iate r ec on st ruc ti on. B il a t e r a l sa l p i ngo - oopho rect o m y f o r BRCA 1 a nd BRCA 2 m u tati on ca rri e r s m ay a l so be c on si d ere d, as t h is p r o ce du re h as b ee n s hown t o r e du c e b r eas t cance r ri sk b y alm o st 50 % T h is is es p eciall y tr u e f o r

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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BR C A2 m u t a ti on ca rri e r s, who te nd t o d e v el op ho rm on e rece p t o r –po siti ve br east c ance r s. Th e second g r oup cons i s t s o f w o me n wit h str ong famil y h ist o ries s ugg esti ve o f he r ed it a r y b r ea st ca n cer w ho test n e g ati v e f o r bo t h t h e BR CA1 a nd BRC A 2 m u t a ti ons as we ll as t h e o t h er d escri b e d s ynd r o mes . I n t h is group, t he r e m ay no t have been a famil y mem b er wit h ca n cer w ho was teste d fo r t he m u t a ti on. T he r e f o re , a n e g ati v e test do es no t n ecessaril y i nd icate t ha t a wo m an ’ s ri sk i s e qu i v ale n t t o t h at o f t h e g e n eral popu lati on .

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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Th e r e ma y a l so be an unde t ec te d m u tati on i n s u c h a famil y , i nd icati ng t he po ssi b ili ty o f h i ghe r -t han - aver a g e ris k f o r t h at p artic u lar w o ma n. T h ese wo me n may o r m ay no t qua li fy f o r e nh a n ce d s u r v eilla n ce wit h MRI sc r ee n i ng and accu r a t e asses sme n t o f t h eir ris k ma y re qu ire t h e u se o f o t h e r r is k p r ed i c ti on t oo l s , i n a dd iti on t o e v al u ati ng f o r t h e p rese n ce o f l obu la r c a r c i no m a i n s it u, a t yp ical l obu lar hyp er p lasia , o r at yp ical du ctal hyp e rp l as i a, and de t e rmi n i ng if a m o re i n te n si v e s u r v eilla n ce re g ime n is n ecessa r y based on he t e r ogeneou sl y o r e x tremel y d e n se b reast tiss u e on mamm og r aph y . Th e t h ir d g r oup cons i s t s o f w o me n wit h a str ong famil y h ist o r y o f b re ast ca n ce r , who f o r va ri ous r eason s , h a v e c ho se n no t t o pu rs u e g e n etic testi ng. Th ese in d i v i dua l s m ay have oth er h ealt h -relate d p r ob lems , p s y c ho l og ica l c on ce rns, cos t i ssues, o r t hey ma y fear p ercei v e d me d ical i n s u ra n ce d isc r imi na ti on. W o m en i n a ll g r oup s ca n b e e du cate d t h at wit h p assa g e o f t h e G e n eti c I n f o rm a ti on Nond iscrimi n ati on Act i n 2008, si gn ifica n t a dv a n ce s have occu rr ed t ha t p r o tect p atie n ts fr o m d iscrimi n ati on by em p l oye r s and hea lt h i nsu r e rs . W o m en i n t he second and th ir d g r oup s ma y still qu alif y f o r b ilateral ri sk - r e du cti on m as t ec t o m y and im m e d iate rec on str u cti on. Ofte n, w o me n w ho elect t h is pa t h a r e i n fl uenced by t h eir famil y h ist o r y o r by wit n essi ng b re ast a nd / or ova ri an cance r dea t hs i n cl o se famil y mem b ers , g i v i ng t h em a si gn i f ic an t f ea r o f a b r eas t o r o v aria n ca n cer d ia gno sis . F o r w o me n i n all t hr ee groups, t he dec i s i on o f wh et h er t o pu rs u e ris k -re du ci ng s u r g er y is d i f f ic u lt . O ft en, t he expe rti se of a ca n cer cli n ical p s y c ho l og ist o r

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Identification of Patients at Risk

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p s y c h iatri s t i s en li s t ed, as ri sk -re du cti on mastect o m y i nvo l v es a n i rr e v e r si b l e p r ocedu r e w it h body ima g e a nd se xu al im p licati on s . Upda t ed i n 2007, t he S oc iet y o f S u r g ical O n c o l ogy pub lis h e d a po siti on stateme n t on t he r o l e o f p r ophy lactic mastect o m y f o r p atie n ts at h i gh ris k for br ea s t cance r , as we ll as t ho se p atie n ts rece n tl y d ia gno se d wit h b reas t ca n ce r who a r e cons i de ri ng con tralateral p r ophy lactic b reast s u r g er y . For wo me n at h i gh ri sk, i nd i ca ti on s fall i n t o t h ree b r o a d cate go ries: p rese n c e o f a m u tati on i n BR C A o r o t he r s u sce p ti b le g e n es , str ong famil y h ist o r y wi th no d em ons tr ab l e m u t a ti on, and h ist o l og ic ris k fact o rs ( b i op s y - p r ov e n at yp ical duc t a l hype r p l as i a, a t yp ical l obu lar hyp er p lasia , o r l obu lar ca r ci noma i n s it u espec i a ll y i n p atie n ts wit h a str ong famil y h ist o r y o f br east c ance r) . Reco mm enda t ion s f o r p atie n ts wit h rece n tl y d ia gno se d br east c ance r a r e s imil a r i n t h at t h e y i n cl ud e t h e i nd icati on s f o r h i gh -ris k i nd i v i du al s p r ev i ous l y no t ed, as well as f u t u re s u r v eilla n ce c h alle ng es f o r t h e oppos it e b r eas t ( c li n i ca ll y a nd mamm og ra ph icall y d e n se b reast tiss u e o r d i f fu se , i nde t e rmi na t e mi c r oc alcificati on s i n t h e c on tralateral b reast) . Ano t h e r im po rt an t cons i de r a ti on is t h e n ee d f o r s y mmetr y i n p atie n ts wi th la r g e , p t o ti c, o r d i sp r opo rti ona tel y size d c on tralateral b reasts .

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Surgical Issues and T echnique

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Surgical Issues and T echnique

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Surgical Issues and T echnique

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In a si ng l e i ns tit u ti on ’ s 33 - ye ar e xp erie n ce , t h e ris k f o r b reast ca n cer in bo t h m ode r a t e - and h i gh -ri sk gr oup s o f w o me n b ase d on famil y h ist o r y was r e du ce d by a t l eas t 89 % f o r wo me n w ho und erwe n t b ilateral p r ophy lacti c mastect o m y . Fr o m a t echn i ca l p ers p ecti v e , i n t h is st ud y , w o me n eit h er had a s ub c u ta neous m as t ec t o m y (r emov al o f t h e maj o rit y o f b reast tiss u e wit h s p a r i ng o f t he n i pp l e–a r eo l a co m p le x ) o r t o tal mastect o m y (rem ov al o f t he e n ti r e breas t t h r ough t he n i pp le – are o la c o m p le x ) . M o st o f t h e rec u rre n c es o cc urr e d i n wo m en unde r go i ng a s ub c u ta n e ou s mastect o m y . H o we v e r , t his w as t h e m os t fr equen t p r ocedu re p erf o rme d at t h at time a nd t hu s ma y h a ve c on t r i buted t o t he nu m be r o f i n crease d rec u rre n ces . Ano t he r su r g i ca l op ti on f or h i gh -ris k w o me n is b ilateral sal p i ngo - oophor e c t o m y . A m ong a coho rt o f w o me n wit h BRCA 1 a nd BRCA 2

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Surgical Issues and T echnique

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PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Surgical Issues and T echnique

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G i v e n a dvances i n r econs tr uc ti v e n i pp le – are o lar tec hn i qu es , it a pp ears t hat t o tal ma s t ec t o m y w it h o r w it hou t s k i n -s p ari ng met hod s re du ces t h e ris k o f br east c ance r t o t he g r ea t es t ex te n t wit h reas on a b le c o smesis . M o re limit ed a nd l ong -t e rm f o ll ow - up da t a are a v aila b le on are o la- a nd n i pp le-s p ari n g tec hn i ques. T he po t en ti a l limitati on s o f t h ese p r o ce du res are d ist o rti on of t h e n i pp l e–a r eo l a co m p l ex and lac k o f se n siti v it y after b reast tiss u e h as b ee n c o m p l e t e l y r e m oved I mme d i a t e r econs tr uc ti on is o f fere d t o p atie n ts a nd p erf o rme d i n t h e vast maj or it y unde r go i ng b il a t e r a l ris k -re du cti on mastect o m y . C ho ices o f r ec on st ruc ti on i nc l ude a b il a teral p e d icle d o r free tiss u e tra n s v erse rect us a bdo mi n i s m usc l e fl ap, a fr ee b ilateral d ee p i n feri o r e p i g astric p erf o rat or f la p or s upe rfi c i a l i n f e ri o r ep i g astric arter y fla p, b ilateral latissim u s fla p s w it h or wit hou t im p l an t o r exp a nd ers , o r b ilateral im p la n t o r e xp a nd er p laceme n t a l one . A lt hough tiss u e fla p tra n sfer g i v es a m o re n at u ral a pp ea r a nce and t ex t u r e t o t he rec on str u cte d site , i nd i v i du al body c on t ou r dr i v es t he u ltim a t e p l an f o r r e c on str u cti on. T h e d ecisi on a bou t t h e t yp e o f r ec on st ruc ti on shou l d be m ade by t h e p lastic s u r g e on wit h i npu t fr o m t he s u r g ical onco l og i s t , espec i a ll y f o r t h e g r oup o f w o me n wit h b reast ca n cer d esi r i ng b il a t e r a l m as t ec t o mies w ho ma y re qu ire a d j uv a n t ra d iati on f o r t r eatme n t .

PA TIENTS A T H IGH RISK F OR BR E AST CANCER

Surgical Issues and T echnique

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A lt hough t he ri sk r educ ti on is d ramatic f o r b ilateral mastect o m y , r esi du al b r eas t ti ssue m ay be left b e h i nd, es p eciall y wit h s k i n -s p ari ng pro ce du r es. P a ti en t s shou l d b e e du cate d t h at caref u l c h est wall s u r v eilla nce is r ec om m ended a ft e r such a p r o ce du re . L o cal rec u rre n ces after b ilateral im p la n t r econs tr uc ti on a r e r e l i a b l y d etecte d by cli n ical e x ami n ati on. Rec urr e nces a ft e r r econs tr uc t ion wit h a u t o l ogou s tiss u e p rese n t m o st c o mm on l y on t he sk i n 50 % t o 72 % o f t h e time a nd are d etecta b le by phy sicia n exa mi na ti on . Nonp al p a b le d ee p er rec u rre n ces i n t h is setti ng a r e less c om m on, and use o f m a mm og ra phy ima g e s u r v eilla n ce ma y b e i nd icated , espec i a ll y if s i gn ifica n t b reast tiss u e was left b e h i nd un i n te n ti ona ll y du ri ng t he b ilateral mastect o m y p r o ce du re . At times , a n i n itial “ sc r een i ng” m a mm og r a m ma y b e p erf o rme d, if si gn ifica n t resi dual br east tis sue i s suspec t ed ; t h i s s hou l d o cc u r well after all h eali ng h as ta k e n p lace t o d e li nea t e t he a m oun t o f v isi b le b reast tiss u e on ima g i ng. T h is dr i v es fu t u r e dec i s i ons o f wh et h er t o f o ll o w a p atie n t wit h ima g i ng. Fi n a ll y , all p atient s shou l d be i ns tr uc t ed t o ret u r n f o r cli n ical b reast e x ami n ati on w it h t h e hea lt h p r ov i de r if any c h a ng e is no te d on t h e rec on str u cte d b reas ts, r e g a rd le ss o f im ag i ng p l an. A lt hough ri sk -r educ ti on b ilateral mastect o m y ma y b e e x cee d i ng l y b e n e f icial f o r h i gh -ri sk wo m e n , es p eciall y f o r t ho se testi ng po siti v e f o r BR C A1 , BR C A 2 , o r o t he r de leteri ou s m u tati on s , o r b el ong i ng t o a famil y a f f licte d w it h a cance r synd r o me , t h e y are n e v er emer g e n t p r o ce du res . A l ong w it h ri sk -r educ ti on b il a teral sal p i ngo - oopho rect o m y , ris k -re du cti on b ilate r al m as t ec t o m y r es i des at t h e far e nd o f t h e s p ectr u m o f a n i nd i v i du al ’ s cho i ces. T hese p r o ce du res s hou l d b e o f fere d on l y after a ppropr iat e gene ti c counse li ng a nd acc u rate assessme n t o f a w o ma n ’ s ac tual r is k for b r eas t and ova ri an can ce r . A n i n - d e p t h c on s u ltati on wit h t h e p atie nt a nd h e r f a mil y m e m be r s i s nec essar y p ri o r t o p r o cee d i ng wit h a n op erati ve p la n.

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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H E REDI T A R Y DIFFUSE GASTRIC CANCER

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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G ast r ic c ance r i s t he f ou rt h m o st c o mm on ca u se o f ca n cer w o rl d wi d e a nd is t h e sec ond l ead i ng cause o f c a n cer m o rtalit y . Alt hough e nv ir on me n tal a g e n ts , i nc l ud i ng He li cobac t er p yl o ri a nd d iet , are t h e p rimar y ris k fact ors for t h is d i sease, app r ox im a t e l y 10 % o f g astric ca n cers are a res u lt o f f amilial c l us t e ri ng . H i s t o l og icall y , g astric ca n cers ma y b e classifie d a s eit h e r i n t es ti na l o r d i f f use t yp es . T h e i n testi n al t yp e h ist op at ho l ogy is li nked t o e nv i ron m en t a l f ac t o r s and a dv a n ce d a g e . T h e d iff u se t yp e o cc u rs i n young e r pa ti en t s and i s assoc iate d wit h a familial p re d is po siti on. Beca u s e o f a d ec r ea se i n i n t es ti na l-t ype ga stric ca n cers , t h e ov erall i n ci d e n ce o f g as t r ic ca n ce r h a s dec li ned s i gn ifi can tl y i n t h e p ast 50 y ears . H o we v e r , t h e i n ci d e n ce o f d i f f use gas tri c c a n cer (DGC) , w h ic h is als o calle d si gn et ri ng cell or li n iti s p l as ti ca, has r e mai n e d sta b le a nd, by s o me re po rts , ma y b e i n c r easi ng. H e r edit a r y DGC ( HDGC ) i s a g e n etic ca n cer s u sce p ti b ilit y s ynd r o me d e f i n e d by one o f t he f o ll ow i ng : ( 1 ) tw o o r m o re do c u me n te d cases o f DG C i n f i r st - o r second - deg r ee r e l a ti v es , wit h at least on e d ia gno se d b ef o re t he a g e of 50 ; o r ( 2 ) t h r ee o r m o re cases o f do c u me n te d DGC i n first- o r sec ond- d eg r ee r e l a ti ves, i ndep e nd e n t o f a g e o f on set . T h e a v era g e a g e o f on set of HDGC i s 38, and t he p atter n o f i nh erita n ce is a u t o s o mal do mi n a n t show s a p e d i g ree wit h HDGC . In 19 9 8, i nac ti va ti ng ge rmli n e m u tati on s i n t h e E-ca dh eri n g e n e CD H1 w e r e i den tifi ed i n t h r ee Mao r i families , eac h wit h m u lti p le cases o f poo rl y d i f f e r e n ti a t ed DGC T he CD H 1 m u tati on s i n t h ese families were i nh eri ted i n a n a utoso m a l do mi nan t pa tter n, wit h i n c o m p lete bu t h i gh p e n etra n ce .

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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On set of c li n i ca ll y appa r en t c a n cer was earl y , wit h t h e young est a f fecte d i nd i v i du al dy i ng o f DGC a t t h e a g e o f 14 Si n ce t h e n, g ermli n e m u tati ons of C DH 1 have been i den tifi ed i n 30 % t o 50 % o f all p atie n ts wit h HDG C Mo r e t han 50 m u tati on s h a v e b ee n rec ogn ize d acr o ss d i v ers e et hn ic backg r ounds, i nc l ud i ng E u r op ea n, Africa n America n, Pa k ista n i , Ja p a n es e, Ko r ean, and o t he r s I n a dd iti on t o g astric ca n cers , g ermli n e C DH1 m u t a ti ons a r e assoc i a te d wit h i n crease d ris k o f l obu lar carci no ma o f t h e br east , and t h i s was t he fi r st ma n ifestati on o f a CDH 1 m u tati on i n o n e se r ies CDH1 i s, t o da t e, t he on l y g e n e im p licate d i n HDGC . Pe n etra n ce o f DG C i n pa ti en t s ca rr y i ng a CD H 1 m u tati on is estimate d at 70 % t o 80 % , but ma y b e h i ghe r . T he need f o r a s y stematic st udy o f s p ecime n s is s uppo rted by r ecent wo r k by Gaya e t a l . i n w h ic h i n itial t o tal g astrect o m y s p ecim ens w e r e r e po rt ed as nega ti ve, bu t d etaile d secti on i ng a nd a n al y sis s ho we d i nv asi v e ca r c i no m a. C DH 1 i s l oca li zed on ch r o m o s o me 16q22.1 a nd e n c od es t h e calci u m -d e p e nd e n t ce ll adhes i on g l ycop r o tei n E-ca dh eri n. F un cti on all y , E-ca dh er in im p acts ma i n t enance o f no rm a l tiss u e m o r pho l ogy a nd cell u lar d i f f e r e n ti a ti on. It i s hypo t hes ize d t h at CDH 1 acts as a t u m o r s upp ress o r g e n e i n H DGC, w it h l oss o f f un cti on lea d i ng t o l o ss o f cell a dh esi on a n d s ub se quen tl y t o p r o lif e r a ti on, i nv asi on, a nd metastases . s hows t h e C D H 1 m u t a ti on f o r t he p e d i g ree d e p icte d i n Th e ge rmli ne CDH1 m u t a ti on is m o st fre qu e n tl y a tr un cati ng m u tati on. G e r mli ne mi ssense m u t a ti ons are ca u sati v e i n a few HDGC k i nd re d s , but

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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a r e m ore o ft en c li n i ca ll y i ns i gn ifica n t . I n v itr o assa y s f o r cell u lar i nv asio n a nd a ggrega ti on m ay p r ed i c t t h e f un cti on al im p act o f misse n se m u tati ons to ai d i n t h i s d i s ti nc ti on . W it h in t h e g astric m u c o sa , t h e “sec ond h it” lea ding t o c o m p l e t e l oss o f E- cadhe ri n f un cti on res u lts fr o m CDH 1 p r o m o ter met hy lati on, as has been desc ri b e d i n s po ra d ic g astric ca n ce r . I t r e ma i ns unc l ea r whe t he r s p ecific CDH 1 m u tati on s are ass o ciate d w ith d isti n cti ve pheno t yp i c cha r act eristics o r rates o f p e n etra n ce , alt hough t h is ma y b ecom e appa r en t as m o r e rec u rre n t m u tati on s are rec ogn ize d. T o date, m o st m u t a ti ons i den tifi ed hav e b ee n nov el a nd d istri bu te d t h r oughou t C DH1 . Recogn iti on o f r ecu rr en t m u tati on s h as u s u all y res u lte d fr o m i nd e p e nden t even t s ; howeve r , t h ere is e v i d e n ce f o r t h e r o le o f f ound er e f f ects in ce rt a i n k i nd r eds At p rese n t , it is als o un clear w h et h er p atie n t s w it h HDGC w it hou t de t ec t abl e CDH 1 m u tati on s h a v e m u tati on o f a d i f f e r e n t gene o r m e r e l y a CD H 1 m u tati on t h at h as gon e un rec ogn ize d. N e w r eco mm ended sc r een i ng criteria f o r CDH 1 m u tati on s are as fo ll ow s: 1. Famili es w it h one o r m o re cases o f DGC 2. Ind i v i dua l s w it h DGC be f o re t h e a g e o f 40 y ears wit hou t a famil y h ist o r y 3. Famili es o r i nd i v i dua l s w it h cases o f DGC ( on e case b el o w t h e a g e o f 50 yea r s ) and l obu l a r b r ea st ca n cer 4. Cases whe r e pa t ho l og i s t s d etect i n sit u si gn et ri ng cells o r p a g et o i d s pr ea d o f s i gne t ri ng ce ll s ad jace n t t o d iff u se t yp e g astric ca n ce , A s i n o t he r f a mili a l cance r s ynd r o mes , g e n etic c oun seli ng s hou l d ta ke p lace prio r t o gene ti c t es ti ng so t h at t h e famil y und ersta nd s t h e po te n tial im p act o f t he r esu lt s. A ft e r o btai n i ng i n f o rme d c on se n t , a team c o m p risi ng a g e n etici s t , gas tr oen t e r o l og i st, s u r g e on, a nd on c o l og ist s hou l d d isc u ss t he po ssi b le ou t co m es o f t es ti ng and t h e ma n a g eme n t op ti on s ass o ciate d wit h eac h. Gene ti c t es ti ng shou l d f i rst b e p erf o rme d on a famil y mem b er with HDG C o r on a ti ssue sa m p l e i f no a f fecte d relati v e is li v i ng. I n a dd iti on to d i r ect se quenc i ng, m u lti p l ex l ig ati on - d e p e nd e n t p r ob e am p lificati on is r ec o mm ended t o t es t f o r l a r g e g e no mic rearra ng eme n ts . If a CDH 1

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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m u tati on i s i den tifi ed, asy m p t o matic famil y mem b ers ma y p r o cee d wit h g e n etic tes ti ng, p r e f e r ab l y by t h e a g e o f 20 . If no m u tati on is i d e n tifie d in t h e f amil y m e m be r w it h DG C , t h e v al u e o f testi ng as y m p t o matic relati ves is l o w . A m ong i nd i v i dua l s f ound t o carr y a g ermli n e CDH 1 m u tati on, cli n ic al sc r ee n i ng i s p r ob l e m a ti c. H i s t o l og icall y , DGC is c h aracterize d by m u lti ple i nf ilt r at es o f m a li gnan t s i gne t ri ng cells , w h ic h ma y und erlie no rmal m u c o sa . Because t hese m a li gn a n t f o ci are small i n size a nd wi d el y d ist r i bu t ed, t hey a r e d i f fi cu lt t o i d e n tif y v ia ra ndo m e ndo sc op ic b i op s y . C hro m oendoscopy and pos itr on emissi on t o m og ra phy h a v e re po rte d l y been u se d, bu t t he c li n i ca l u tilit y of t h ese t oo ls i n earl y d etecti on remai n s unprov e n. L ack o f a sens iti ve scree n i ng test f o r HDGC ma k es earl y d ia gno sis ex tr e m e l y cha ll eng i ng. B y t h e time p atie n ts are s y m p t o matic a nd pr ese n t f o r tr ea tm en t , m any h a v e d i f f u se i nvo l v eme n t o f t h e st o mac h o r li n itis p l as ti ca, and r a t es o f mortalit y are h i gh. P ub lis h e d case re po rts d esc r i b e pa ti en t s who have p rese n te d wit h e x te n si v e DGC d es p ite rece nt nor mal e ndoscopy and nega ti v e b i op sies . T h e 5 - y ear s u r v i v al rate f o r i nd i v i du al s who deve l op c li n icall y a pp are n t DGC is on l y 10 % , wit h t h e maj or it y dy i ng be f o r e age 40. Beca use o f h i gh cance r pen etra n ce , poo r ou tc o me , a nd i n a d e qu ac y o f cli n ical s c r een i ng t oo l s f o r HD GC , p r ophy lactic t o tal g astrect o m y is r ec o mm ended as a m anage m en t op ti on f o r as y m p t o matic carriers o f CD H1 m u tati ons . A lt hough t o t a l ga strect o m y is p erf o rme d wit h p r ophy lactic i n te n t i n t hese cases, m os t spe cime n s h a v e b ee n f ound t o c on tai n f o ci o f d i f fu se si gne t ri ng ce ll cance r . F o ci o f DGC h a v e b ee n i d e n tifie d e ven i n p atie n t s who have unde r gon e e x te n si v e n e g ati v e scree n i ng, i n cl ud i ng h i gh-r es o l u ti on co m pu t ed t omog ra ph y , po sitr on emissi on t o m og ra phy s can, c hro m oendoscopy - gu i ded b i op sies , a nd e ndo sc op ic u ltras onog ra ph y

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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H E REDI T A R Y DIFFUSE GASTRIC CANCER

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How e v e r , HGDC i n asy m p t o matic CDH 1 carriers is u s u all y c o m p letel y r esecte d by p r ophy l ac ti c gas t r ect o m y , as p at ho l og ic a n al y ses o f resecte d s p ecime ns have shown on l y T 1 N 0 d isease . Beca use t hese s i gne t ri ng c ell ca n cers are m u ltif o cal a nd d istri bu te d t hroughou t t he en tir e s t o m ach, es p eciall y i n t h e car d ia , p r ophy lactic

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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g ast r ect o m y shou l d i nc l ude t h e e n tire st o mac h, a nd t h e s u r g e on m u st t r a n sect t he esophagus and not t h e p r ox imal st o mac h. F u rt h erm o re , it s hou l d b e pe rf o rm ed by a su r g e on e xp erie n ce d i n t h e tec hn ical as p ects o f t h e pro c edu r e and f a mili a r w i th HDGC . I n as y m p t o matic p atie n ts , l y m ph nod e m e t as t ases have no t been ob ser v e d ; t h eref o re , D 2 l y m ph nod e r esecti on i s no t necessa r y . T h e op timal timi ng o f p r ophy lactic g astrect omy i n i nd i v id ua l s w it h CDH1 m u tati on s is unkno w n, bu t rece n t c on se n s u s r ec o mm enda ti ons i nd i ca t e t h at a g e 20 is reas on a b le . A lt hough it i s a po t en ti a lly lifesa v i ng p r o ce du re , p r ophy lactic g ast r ect o m y f o r CDH1 m u t a ti on carries si gn ifica n t ris k s t h at m u st b e c on si d e red. Ove r a ll m o rt a lit y f o r t o tal g astrect o m y is estimate d t o b e as h i gh as 2 % t o 4 % , a lt hough it is estimate d t o b e 1 % w h e n p erf o rme d prophy l ac ti ca ll y . P a ti en t s m us t als o b e aware t h at t h ere is a n earl y 100 % r is k of l ong -t e rm m o r b i d it y a ss o ciate d wit h t h is p r o ce du re , i n cl ud i ng d ia rrh ea , du m p i ng, we i gh t l o ss , a nd d i f fic u lt y eati ng . A rece n t st udy o f the e f f ects o f p r ophy l ac ti c gas tr ec t o m y f o r CDH 1 m u tati on d em on strate d t hat phy sical and m en t a l f unc ti on were no rmal at 12 m on t h s , bu t s p ecific d i g esti v e i ssues we r e r ecogn ize d. O v erall , 70 % h a d d iarr h ea , 63 % fati g u e, 81% eati ng d i sco mf o rt , 63 % refl ux, 45 % eati ng restricti on s , a nd 44 % had alte r e d b ody im age, sugges ti n g t h at t h is op erati on im p acte d n e g ati v el y on qu alit y o f lif e . Because o f these c o m p licati on s a nd t h e fact t h at l y m ph nod e s p r ead has no t been obs er v e d, s o me rec o mme nd v a gu s- p reser v i ng g ast r ect o m y done e it he r open o r la p ar o sc op icall y . I n a dd iti on, b eca u se t he p e n et r an ce o f CDH1 m u t a ti on s is i n c o m p lete , s o me p atie n ts w ho und er go prophy l ac ti c gas tr ec t o m y wou l d n e v er h a v e gon e on t o d e v el op cli n icall y si gn i f ic an t gas tri c cance r . Pr ophy lactic g astrect o m y h as , i n fact , b ee n p e rfor me d on seve r a l pa ti en t s re po rte d t o s ho w no e v i d e n ce o f g astric ca n ce r on pa t ho l og y . S o m e i nd i v i dua l s w it h CD H 1 m u tati on s c hoo se no t t o pu rs u e prophy l ac ti c gas tr ec t o m y . T h ese i nd i v i du als s hou l d und e r go caref u l s urv eill ance, i nc l ud i ng b i ann ual c h r o m o e ndo sc opy wit h b i op sies , b e g i nning wh e n t h e y a r e a t l eas t 10 yea rs young er t h a n t h e young est famil y mem be r w it h DGC was a t tim e o f d i agno sis . It is rec o mme nd e d t h at a ny

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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e ndo sc op i ca ll y v i s i b l e l es i on i s tar g ete d a nd t h at si x ra ndo m b i op sies ar e ta k e n fro m t he f o ll ow i ng r eg io n s: a n tr u m , tra n siti on al z on e , bod y , f undus, a nd ca rd i a. Ca r e f u l wh it e -li gh t e x ami n ati on wit h ta r g ete d a nd ra ndo m b i op sies co m b i ned w it h de t a i l e d h ist op at ho l ogy ca n i d e n tif y earl y lesi ons a nd h el p t o i n f o rm dec i s i on ma k i ng wit h re g ar d t o g astrect o m y

H E REDI T A R Y DIFFUSE GASTRIC CANCER

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H E REDI T A R Y DIFFUSE GASTRIC CANCER

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Add iti ona ll y , because wo m en wit h CDH 1 m u tati on s h a v e a n earl y 40 % li f etime ri sk o f deve l op i ng l obu lar b reast carci no ma , t h e y s hou l d b e ca r e fu ll y sc r eened w it h annu al mamm og ra phy a nd b reast MRI starti ng at a g e 35 T hey shou l d a l so do m on t h l y self-e x ami n ati on s a nd h a v e a b re ast e x ami n a t i on by a phys i c i an ev er y 6 m on t h s . T h e same s u r v eilla n ce r ec o mm enda ti ons a r e p r obab l y a pp r op riate f o r HDGC families wit hou t i d e n ti f ia b l e CDH1 m u t a ti ons, alt hough no c u rre n t gu i d eli n es f o r t h is e x is t. Th e e m e r gence o f gene - d irecte d g astrect o m y as a treatme n t strate gy fo r p atie n ts wit h HDGC r ep r esen ts t h e c u lmi n ati on o f a s u ccessf u l c o lla bora ti on be t ween m o l ecu lar b i o l og ists , g e n eticists , on c o l og ists , g ast ro e n t e r o l og i s t s, and su r geon s . It is a n tici p ate d t h at t h e rec ogn iti on o f simila r m o l ecu l a r m a r ke r s i n o t h er familial ca n cer s ynd r o mes will t r a n s form t he app r oach t o t he earl y d ia gno sis a nd treatme n t o f a v ariet y o f t u m or s .

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

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SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

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He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

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popu lati ons ( <1 i n 500 i nd i v i du als); on e no ta b le e x ce p ti on is t h e As hk e nazi Je w is h popu l a ti on, i n wh i ch the carrier fre qu e n c y is 1 i n 40 . BRCA 1 - ass o ciate d cases peak i n t he 5 0s a nd BRCA 2 -ass o ciate d ca n cers i n t h e 60s .

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

In a dd iti on t o BR C A 1 / 2 m u t a ti on s , g ermli n e m u tati on s i n a nu m b er o f o t he r g e n es i n t he ho m o l ogous r eco m b i n ati on DNA re p air p at h wa y c on fer h i gh p e n et r an ce suscep ti b ilit y t o ov aria n ca n cer (e .g., RAD 51 C , RAD 51 D , BRIP1 , P ALB 2 ) . T h i s has l ed t o t h e d e v el op me n t o f m o re c o m p re h e n siv e ca n ce r g e ne ti c t es ti ng pane l s t h at are i n creasi ng l y b ei ng u se d t o i d e n tif y wo me n w ho a r e cand i da t es f o r ris k -re du ci ng sal p i ngo - oopho rect o m y ( RR SO). G e n e t i c t es ti ng f o r i nhe rite d h i gh - p e n etra n ce m u tati on s i n BRCA 1 / 2 and o t h e r g e nes shou l d be d i scuss e d wit h w o me n w ho h a v e a si gn ifica n t fa mily h ist ory o f ea rl y onse t b r eas t c a n cer a nd / o r ca n cers o f t h e ov ar y , fall op ian t ub e , or pe rit oneu m . I nvo l ve me n t o f a g e n etic c oun sel o r p ri o r t o testi ng is h el pfu l , a s t hey have expe rti s e i n ma n a g i ng t h e i nh ere n t cli n ical a nd s o c ial iss u es . M os t BR C A 1 / 2 m u t a ti on s i nvo l v e b ase d eleti on s o r i n serti on s i n t he c od i ng se quence o r sp li ce s it es t h at e n c od e tr un cate d p r o tei n p r odu cts t hat a r e clearl y dys f unc ti ona l . L es s fre qu e n tl y , d isease-ca u si ng m u tati on s ma y o cc ur t ha t a lt e r a s i ng l e a mi no aci d, t hough m o st o f t h ese misse n se v aria nts r e pr ese nt i nnocen t po l y m o r ph isms . T h e cli n ical si gn ifica n ce o f misse n se m u tati ons can so m e tim es be el u ci d ate d by d etermi n i ng w h et h er t h e y se gr e g at e w it h cance r i n o t her famil y mem b ers . I n a dd iti on, g e no mic r ea rr a nge m en t s m ay occu r t h at i n acti v ate BRCA 1 o r BRCA 2 , a nd i d e n ti f ic a ti on o f such a lt e r a ti on s re qu ires m o lec u lar testi ng b e yond se qu e n ci ng. Pe n e t r ance o f ova ri an can cer is no t 100 % i n t ho se wit h clearl y d elete r i ous BR C A 1 / 2 m u t a ti on s , bu t p rese n tl y it is no t po ssi b le t o p r ov i de m or e pr e c i se pe r sona li zed ri sk estimates t o gu i d e t h e u se o f RRSO . How e v e r , co mm on va ri an t s hav e b ee n d isc ov ere d i n o t h er g e n es t h at a ppea r t o a f f ect t he ri sk o f ova ri an c a n cer i n BRCA 1 / 2 carriers . Base d on t h e known ova ri an cance r ri sk– m od if y i ng l o ci , it h as b ee n re po rte d t h at t h e 5% of BR C A1 ca rri e r s a t l owes t r i s k h a v e a lifetime ris k o f ≤28 % o f d e v el oping ov a r ia n cance r , whe r eas t he 5% at h i gh est ris k h a v e a ≥63 % lifetime ris k. I n

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

t h e fu t ure, when m od ifi e r l oc i are m o re c o m p letel y catal ogu e d, m o re pr ecise es tim a t es o f cance r ri sk ma y b e p r ov i d e d t o i nd i v i du al p atie n ts who a r e c on si de ri ng RR S O. A s a bou t 20 % o f wo m en wit h h i gh - g ra d e ser ou s ov aria n ca n cers h a ve BR C A1 / 2 m u t a ti ons, it has be e n s ugg este d t h at all o f t h ese w o me n und e r go g e n etic tes ti ng r ega r d l ess o f f a mil y h ist o r y . M u tati on al a n al y sis i n w omen w it h t h e se cance r s m ay i nc r ea si ng l y b ec o me sta nd ar d p ractice as t h e c o s t o f g e n etic tes ti ng dec li nes. T es tin g ma y als o b e d ri v e n by t h e a v aila b ilit y of po l y(AD P-ri bose ) po l y m e r as e i nh i b it o r t h era py f o r w o me n w ho se ca n ce rs h a v e g ermli ne o r spo r ad i c m u tati on s i n g e n es s u c h as BRCA 1 / 2 a nd o t he r s t h at a r e invo l ved i n ho m o l ogou s rec o m b i n ati on DNA re p ai r . RRSO i s s tr ong l y r eco mm end e d i n w o me n w ho carr y BRCA 1 / 2 m u tati ons because o f t he h i gh m o rtalit y rate o f ov aria n ca n cer a nd t h e la ck of e f f ecti ve sc r een i ng and p r ev e n ti on a pp r o ac h es . Alt hough scree n i ng w ith p el v ic u ltr asound and se r u m CA 125 is g e n erall y rec o mme nd e d f o r BR C A1 / 2 ca rri e r s du ri ng t he ir 20 s a nd 30 s , it is no t p r ov e n t o re du ce ov a r ia n cance r m o rt a lit y becau se e v e n earl y sta g e h i gh - g ra d e ca n cers h av e a v e ry h i gh m o rt a lit y . O r a l con trace p ti v es re du ce t h e ris k o f ov aria n ca nce r i n t h e gene r a l popu l a ti on and a pp ear t o h a v e a similar effect i n BRCA 1 / 2 ca rr ie r s , bu t t h i s m us t be ba l an ce d a g ai n st c on cer n s re g ar d i ng i n crease d br east c ance r ri sks. Th e pas t p r ac ti ce o f pe rf o rmi ng RRSO b ase d s o lel y on famil y h ist o ry h as b ee n r ep l aced by r e li ance on g e n etic testi ng. Cli n ical ma n a g eme n t o f wo me n wit h a s tr ong f a mil y h ist o r y i n w ho m a d eleteri ou s g ermli n e m u tati on i s no t f ound, o r t hose wit h v aria n ts o f un certai n si gn ifica n ce , s hou l d b e r eso l ved on a case - by -case b asis . RRSO ma y b e d eeme d a ppropr iat e i n so m e cases, de s p ite t h e a b se n ce o f a clearl y d eleteri ou s m u tati on. F o rt una t e l y , t he ri s k o f h ere d itar y ov aria n ca n cer do es no t rise dr amati ca ll y un til t he mi d - 30 s i n w o me n wit h BRCA 1 m u tati on s a nd t h e 40 s for wo m en w it h BR C A 2 m u tati on s . As a res u lt , m o st w o me n are a ble t o c o m p l e t e ch il dbea ri ng p ri or t o und e r go i ng RRSO . It is a dv isa b le f o r BR C A1 ca rri e r s t o unde r go RR SO ar ound a g e 35, as t h ere is a 4 % ris k o f ov a r ia n cance r be i ng d i scove re d cli n icall y o r at t h e time o f RRSO by a ge

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

40. BRC A 2 ca rri e r s m ay ch o o se t o d ela y s u r g er y i n t o t h eir 40 s du e t o t hei r l ow e r r is k o f ova ri an cance r , bu t t h is c ou l d d imi n is h t h e p r o tecti on a g ai nst br east c ance r t ha t i s a f f o r ded by RRSO . If a m u tati on carrie r , p artic u larl y a BR C A1 ca rri e r , chooses t o pu rs u e fertilit y i n t o h er 40 s , t h e n s h e s hou l d be c oun sel ed t ha t she i s a t cons idera b le ris k o f d e v el op i ng a life-t h reate n i ng ca n ce r t ha t i s l a r ge l y p r even ta b le . Se v e ra l s t ud i es have p r ov i d e d e v i d e n ce o f t h e efficac y o f RRSO . I n one ea r l y stu dy o f BR C A 1 / 2 ca rriers , RRSO re du ce d t h e rate o f b reast a nd ov a r ia n cance r by 75 % ove r s e v eral y ears o f f o ll o w- up A se p arate st udy i n 2002 exa mi ned ou t co m e i n 551 BRCA 1 / 2 carriers fr o m v ari ou s r e g ist r ie s . A m ong 259 wo me n w ho h a d und e r gon e RRSO , 6 ( 2.3 %) w e r e found t o have s t age I ova ri an ca n cer at t h e time o f t h e p r o ce du re a nd 2 (0.8%) s ubsequen tl y deve l op e d ser ou s p erit on eal carci no ma . Am ong t h e c on t ro ls , 58 ( 20 %) wo m en dev el op e d ov aria n ca n cer after a mea n f o ll ow - up of 8.8 y e a r s. W it h t he exc l us i on o f t h e si x w o me n w ho se ca n cers were d ia gno se d a t su r ge r y , RR S O re du ce d ov aria n ca n cer ris k by 96 % . M o re r ece n tl y , i n 2014, an i n t e r na ti on al re g istr y st udy o f ov er 5,783 s ub jects with me d ia n f o ll ow - up o f 5.6 yea rs f ound t h at RRSO re du ce d ov aria n, t ub al , and p e r it on e a l cance r ri sk by 80 % T h ere was a n estimate d lifetime ris k o f pr ima ry pe rit onea l cance r a fter RRSO o f a bou t 4 % f o r BRCA 1 carriers a nd 2% for BR C A 2 ca rri e r s . T he ris k o f d eat h fr o m all ca u ses was re du ce d by 77%. A p r ospec ti ve coho rt s t udy no te d t h at RRSO was ass o ciate d wit h r e du cti on i n b r eas t cance r –sp ecific ( h azar d rati o [HR] = 0.44 ; 95 % c onf i d e nce i n t e r va l [ C I] = 0.26 t o 0.76 ) , ov aria n ca n cer – s p ecific (HR = 0.21 ; 95 % C I = 0.06 t o 0.80 ) , a nd all-ca u se m o rtalit y (HR = 0.40 ; 95 % C I = 0.26 t o 0.61 ) . Rem ova l o f t he ova ri es, as i n ter n al o r g a n s , u s u all y h as little e f fect on body im age and se lf- es t ee m , and m o st BRCA 1 / 2 m u tati on carriers elect t o und e r go RR S O. I nsu r ance pa yers will alm o st alwa y s p a y f o r RRSO i n prov e n m u t a ti on ca rri e r s. RRSO can be pe rf o rm ed la p ar o sc op icall y i n m o st w o me n, wit h d isc h a r ge t o ho m e t he sa m e da y . If a la p ar o sc op ic a pp r o ac h is p r ob lema tic du e t o obes it y o r adhes i ons, t h e s u r g er y ca n b e p erf o rme d t h r ough a sma ll

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

l ow e r a bdo mi na l i nc i s i on. Mo r b i d it y i n cl ud i ng b lee d i ng, i n fecti on, a nd d ama g e to t he u ri na r y o r gas tr o i n testi n al tracts ca n o cc u r , bu t t h e i n ci d e nce of se r i ous co m p li ca ti ons i s very l o w . As t h e fall op ia n t ub es a nd ov aries a r e small d i sc r e t e o r gans, t hey a r e relati v el y eas y t o rem ov e c o m p letel y . A tte n ti on shou l d be pa i d t o tra n secti ng t h e ov aria n arter y a nd v ei n p r ox i mal t o t h e ova r y and t ube so t ha t r e m n a n ts are no t left b e h i nd. T h is i nvo l v es op e n i ng t he pe l v i c s i dewa ll pe rit on e u m , v is u alizi ng t h e u rete r , a nd t h e n is o lati ng t he ova ri an b l ood supp l y . If t h ere are a dh esi on s b etwee n t h e a dn e x a and ad j acen t s tr uc t u r e s , caref u l d issecti on s hou l d b e p erf o rme d to e n s ur e c o m p l e t e r e m ova l o f t h e ov aries a nd fall op ia n t ub es . If t h e u ter u s is no t r em oved, ca r e shou l d be t ak e n t o rem ov e t h e e n tire fall op ia n t ub e . A small po rti on o f t he t ube i nev ita b l y will b e left i n t h e c o r nu o f t h e u ter u s , bu t t h e risk o f f a ll op i an t ube ca n cer d e v el op i ng i n s u c h rem n a n ts a pp ear s to b e n e g li g i b l e. Though t he r e i s no t s tr ong e v i d e n ce t h at BRCA 1 / 2 m u tati on s i n crease u te r i n e cance r ri sk, m any wo me n elect t o h a v e t h e u ter u s rem ov e d as p ar t o f t h e s u r g i ca l p r ocedu r e becaus e t h e y h a v e c o m p lete d t h eir famil y o r h a v e o t h e r gyneco l og i c i nd i ca ti ons. Alt hough t h e a dd iti on o f a hy sterect o m y may i n c r ease ope r a ti ve tim e, b l ood l o ss , s u r g ical c o m p licati on s , a nd ho s p ital sta y , it usua ll y can be pe rf o rme d la p ar o sc op icall y a nd seri ou s a dv erse ou tc o m es a r e i n fr equen t . F u rt h erm o re , t h e li k eli hood o f f u t u re e xpo s u re to tam ox i fen i n t he con t ex t o f b r e ast ca n cer p re v e n ti on o r treatme n t , w h ic h i n c r ease s endo m e tri a l cance r ris k tw o - t o t h ree-f o l d, als o a r gu es f o r c on c o m i t an t hys t e r ec t o m y . W o me n w ho recei v e ho rm on e re p laceme n t t h e r a py a ft e r su r ge r y w ill r equ ire a p r og esti n al ong wit h estr og e n t o p r o te ct a g ai n st th e deve l op m en t o f endo metrial ca n cer if t h e u ter u s is no t rem oved. In yo u nge r wo m en, su r g i c al me nop a u se after RRSO is ass o ciate d wit h v as o m o t o r sy m p t o m s, vag i na l atr oph y , d ecrease d li b i do, a nd a n accelerat ed on set a nd i nc i dence o f os t eopo r o sis a nd car d i ov asc u lar d isease . I n pr eme nopausa l wo m en who do no t h a v e a p ers on al h ist o r y o f b reast ca nce r , est rog e n r ep l ace m en t can be a d mi n istere d t o ameli o rate ma ny o f t h e d elete r i ous e f f ec t s o f p r e m a t u re me nop a u se . S y stemic estr og e n le v els ar e l ow e r i n oopho r ec t o mi zed p reme nop a u sal w o me n ta k i ng ho rm on e

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

r e p lacem en t t han if t he ova ri es h a d b ee n left i n p lace . T h e t h era p e u tic b e n e f it o f oopho r ec t o m y i n w ome n wit h b reast ca n cer h as l ong b ee n a ppr eciat ed, and m o r e r ecen t st ud ies s uppo rt t h e c on te n ti on t h at RRSO r e du ces t he ri sk o f b r eas t canc er by a bou t h alf i n BRCA 1 / 2 carriers

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

How e v e r , a m e t a - ana l ys i s sho we d t h at w h ile RRSO was str ong l y p r o tect ive a g ai n st es tr ogen r ecep t o r –pos iti v e b reast ca n cer (HR = 0.22 ) , t h ere was no pro tecti on aga i ns t es tr ogen r e ce p t o r –n e g ati v e b reast ca n ce r Ma ny carr ie r s a r e i d e nt ifi ed a ft e r deve l op i n g earl y on set b reast ca n ce r , a nd t h is g r oup r e pr ese nts t he m os t d i f fi cu lt i n w h ic h t o b ala n ce t h e po te n tial ris k s a nd b e n e f its o f es tr ogen r ep l ace me n t t h era p y . E a r l y s t age h i gh - g r ade se r ou s ca n cers a nd i n sit u lesi on s wit h TP 53 m u tati ons have been i den tifi ed i n t h e fall op ia n t ub es o f s o me RRSO s p ecime ns ( ) . T h i s ha s le d t o a p ara d i g m s h ift i n w h ic h it is now t hough t t ha t m os t h i gh - g r ade ser ou s ca n cers f ound i n t h e ov ar y , fall op ian t ub e , a nd pe rit oneu m a r e de ri v e d fr o m cells t h at o ri g i n ate i n t h e t ub al f im br ia . T he fr equency o f oc c u lt mali gn a n cies h as v arie d b etwee n re po r ts, bu t a ppea r s t o be abou t 3 % . I n v iew o f t h is , t h e p el v is a nd p erit on eal ca v it y s hou l d be exa mi ned ca ref u ll y . Mali gn a n t cells als o h a v e b ee n f ound i n p e r it onea l cy t o l og i c spec ime n s , a nd was h i ng s o f t h e p el v is s hou l d b e ob tai n e d when pe rf o rmi ng R RSO . T h e p at ho l og ist s hou l d b e i n f o rme d o f t h e i nd i ca ti on f o r su r ge r y and serial secti on s o f t h e fall op ia n t ub es s hou l d be p e rfor me d t o l ook f o r t he p r e se n ce o f earl y lesi on s . Patie n ts f ound t o h a ve o cc u lt i nvas i ve h i gh - g r ade se r ou s ca n cers s hou l d b e treate d wit h c h em o t he r apy a ft e r su r ge r y . T ho se wit h i n sit u lesi on s a pp ear t o h a v e a good ou t co m e w it hou t che m oth era p y .

SURGICAL PROPHY L AXIS O F HE REDI T A R Y O V ARIAN AND E ND OMET RIAL CAN C ER

He r editary Ovarian Cancer ( BRCA 1 , BRCA 2 )

nan nan

Cases o f pe rit onea l se r ous carci no ma i nd isti ngu is h a b le fr o m ov aria n ca n ce r h a ve been obse r ved ye ars after RRSO , bu t t h e o ri g i n o f t h ese ca n ce r s i s unc l ea r . S o m e m ay re p rese n t rec u rre n ces o f o cc u lt ov aria n o r t ub al can ce r s. I n t h i s r ega r d, retr o s p ecti v e e x ami n ati on o f t h e ov aries a nd f all op ia n t ubes so m e tim es has re v eale d p rimar y ca n cers t h at were no t or i g i n all y r ecogn i zed. I n con t r ast , s o me o f t h ese ca n cers li k el y arise d irec tly fro m f all op i an t ube ce ll s t ha t ha v e im p la n te d i n t h e p erit on e u m a nd s ub se quen tl y beco m e m a li gnan t . Patie n ts w ho und er go RRSO s hou l d b e ma d e aw a r e o f t he ir r es i dua l ris k o f p erit on eal ca n ce r , bu t t h ere is no e v i d e n ce t ha t con ti nued su r ve illa n ce u si ng CA 125 a nd / o r u ltras ound is b e n e f icial .

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

A lt hough L ynch synd r o m e (L S, als o kno w n as h ere d itar y nonpo l ypo sis CRC s y n d r o m e ) t yp i ca ll y m an ifests as familial cl u steri ng o f earl y on set CRC , t he r e i s a l so an i nc r eased i n ci d e n ce o f se v eral o t h er t yp es o f ca n cer s — m o st no t ab l y endo m e tri a l c a n cer i n w o me n . A bou t 3 % o f e ndo metria l ca n ce r s a r e a ttri bu t ab l e t o i nh erite d m u tati on s i n t h e DNA mismatc h re pai r ( MMR ) genes t ha t cause LS . M o st o fte n, M S H 2 a nd MLH 1 are im p licat ed, bu t m u tati ons i n M SH6 and PM S2 als o o cc u r T h e ris k o f ov aria n ca n c e r is

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

als o si gn ifi can tl y i nc r eased i n LS , bu t t o a lesser d e g ree t h a n i n BRCA 1 / 2 m u tati on ca rri e r s, and accoun ts f o r on l y a bou t 1 % o f all ov aria n ca n cers . Cells i n wh i ch one o f t he LS g e n es h a v e b ee n i n acti v ate d e xh i b it a ph e no m enon ca ll ed mi c r osa t e llite i n sta b ilit y (MSI) . T h is o cc u rs as DN A mismatch es cause sho rt en i ng o r le ng t h e n i ng o f re p etiti v e DNA se qu e n c es a nd t h es e mi s m a t ches go un r ep aire d. T h is res u lts i n g e n erati on o f alleles in t h e ca n c e r t ha t con t a i n a g r eat er o r lesser nu m b er o f re p eats t h a n are p re sent i n nor mal ce ll s fr o m t ha t i nd i v i du al . MSI o cc u rs i n m o st LS-ass o ciate d c o l or ectal and endo m e tri a l can cers . H o we v e r , MSI is f ound i n a bou t 20 % of s por a d i c cance r s t ha t a ri se in t h ese o r g a n s , a nd i n m o st cases is ca u se d by sile n ci n g o f t he ML H1 gene du e t o p r o m o ter hyp ermet hy lati on. Scree n i ng st r ate g ie s f o r i den tifi ca ti on o f MMR g e n e alterati on s i n families wit h L S -ass o ciate d cance r s i nc l ude an al y sis o f t u m o r tiss u e f o r MSI a nd / o r l o ss o f DNA M MR gene exp r ess i on u si ng imm unoh ist o c h emistr y (IHC) . I n ca n ce r s w it h M SI o r l oss o f e x p ressi on o f on e o f t h e MMR g e n es , o r i n f amilies w it h ped i g r ees sugge sti v e o f LS , t h ese g e n es ca n b e se qu e n ce d to i d e n ti fy d i sease - caus i ng m u t at i on s , m o st o f w h ic h ca u se tr un cate d p r o te in produ ct s. A lt hough it has been s ugg este d t h at it ma y b e c o st-effecti v e t o do t h ese t es t s on a ll endo m e trial ca n cers , t h is a pp r o ac h h as no t b ee n wi d e ly a dop te d. Th e risk o f a wo m an who carries a LS m u tati on d e v el op i ng e ndo metr ial ca n ce r r a nges fr o m 20 % t o 60 % i n v ari ou s re po rts . T h e ris k o f ov ari an ca n ce r i s i nc r eased t o abou t 5 % t o 12 % . W h ereas t h e mea n a g e o f w o m en w it h s po r ad i c endo m e tri a l can cers is i n t h e earl y 60 s , ca n cers t h at arise i n ass o ciat ion w it h LS a r e o ft en d ia gno se d b ef o re me nop a u se , wit h t h e a v e r a g e age i n t he 40s. T he c l in ical feat u res o f t h ese e ndo metrial ca n cer s a r e simi la r t o t hose o f m os t spo ra d ic cases (well- d iffere n tiate d, e ndo me t ri o i d h i s t o l og y , ea rl y sta g e) , a nd s u r v i v al is a bou t 90 % . T h e me an a g e of onse t o f ova ri an cance r i n LS is i n t h e earl y 40 s , a nd t h e cli n ical f eat ur es o f t hese cance r s a r e g e n erall y m o re fa vo ra b le t h a n i n s po ra d ic cases . They usua ll y a r e i den ti f ie d at a n earl y sta g e , are well- o r m od erat ely d i f f e r e n ti a t ed, have f avo r ab l e s u r v i v al , a nd s o me o cc u r i n t h e setti ng o f a s yn c hronous endo m e tri a l can ce r .

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

Rec o mm enda ti ons f o r sc r e e n i ng a nd ris k -re du ci ng s u r g er y i n LS are b ette r est ab li shed f o r CRC t han f o r e x trac o l on ic mali gn a n cies .

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

T r a n s v a g i na l u ltr asound has b ee n p r opo se d as a scree n i ng test f o r e ndo me t ri a l cance r ( and ova r i a n ca n cer) , bu t its efficac y is unp r ov e n .

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

H E REDI T A R Y E ND OMET RIAL CAN C ER ( L YNCH SYNDR OME )

nan nan

Endo metri a l b i opsy i s t he m o st se n siti v e mea n s o f d ia gno si ng e ndo metria l ca n ce r , and it has been sugges te d t h at t h is s hou l d b e em p l oy e d p eri od ica lly b e g i nn i ng a r ound age 30 t o 35. H o we v e r , t h ere are no pub lis h e d st ud ies d em on st ra ti ng t ha t t h i s app r o ac h p re v e n ts e ndo metrial ca n cer d eat h s c o m p a red t o s im p l y pe rf o rmi ng a b i op s y if a bno rmal u teri n e b lee d i ng o cc ur s . M o st expe rt s be li eve t ha t ris k -re du ci ng hy sterect o m y h as a r o le i n t he ma n a g e men t o f so m e wo m en wit h LS b eca u se o f t h e h i gh i n ci d e n ce o f e ndo me t ri a l cance r . T he ri sk o f e ndo metrial ca n cer is l o w du ri ng t h e p ri me r e produ cti ve yea r s, and t he u ter u s do es no t ser v e a v ital f un cti on on ce c h il db ea r i ng has been co m p l e te d. I n v iew o f t h e i n crease d ris k o f ov arian ca n ce r i n LS , conco mit an t b il a teral sal p i ngo - oopho rect o m y s hou l d als o be c on si d e red. One s t udy de m on strate d t h at t h ere were no cases o f e ndo me t r ial or ov a r ia n cance r i n 61 LS car riers w ho und erwe n t ris k -re du ci ng hy ste r ect o m y and b il a t e r a l salp i ngo - oopho rect o m y , w h ile e ndo metrial ca n ce r o c cu rr ed i n 33 % and ov aria n ca n cer i n 5 % w ho retai n e d t h eir u ter us a nd ov a r i es Desp it e t he l ow ris k o f d eat h fr o m gyn ec o l og ic ca n cers i n LS, c o st - e f f e c ti veness ana l yses o f v ari ou s a pp r o ac h es s ugg est t h at ris k -re ducing hy ste r ect o m y and sa l p i ngo - o o pho rect o m y lea d s t o bo t h t h e l o west c o st and t h e gr ea tes t i nc r ease i n qua lit y -a d j u ste d life- y ears . Estr og e n re p laceme nt a f te r r em ova l o f t he ova ri es i n p reme nop a u sal w o me n wit h LS is no t c on t r ai nd i ca t ed, as t he r e i s no e v i d e n ce t h at t h is a dv ersel y a f fects t h e i n ci d e n ce o f o t he r cance r s. Ma ny wo m en w it h LS e l ec t t o und e r go ris k -re du ci ng c o lect o m y , w h i ch prov i d e s an oppo rt un it y t o pe rf o rm c on c o mita n t hy sterect o m y . Hy ste r e c t o m y i n conce rt w it h c o lect o m y , eit h er v ia la p ar o sc opy o r la p a ro t o m y , does no t g r ea tl y i n crease op erati v e time o r s u r g ical c o m p lic a ti ons. If an endo m e trial b i op s y h as no t b ee n p erf o rme d pr e op e ra ti ve l y , an i n tr aope r a t iv e i n s p ecti on o f t h e u teri n e ca v it y a nd

GYNECOLOGIC CANC E R RISK IN V E R Y RARE HE REDI T A R Y CANC E R SYNDROMES

nan nan

GYNECOLOGIC CANC E R RISK IN V E R Y RARE HE REDI T A R Y CANC E R SYNDROMES

GYNECOLOGIC CANC E R RISK IN V E R Y RARE HE REDI T A R Y CANC E R SYNDROMES

nan nan

Se v e r al ve r y r a r e he r ed it a r y c a n cer s ynd r o mes als o i n crease t h e ris k o f gyn ec o l og i c cance r s, and so me o f t h ese w o me n c ou l d po te n tiall y b e n efi t fro m r is k -r educ i ng su r ge r y t o rem ov e t h e ov aries a nd / o r u ter u s . Pe u tz-Je gh e r s synd r o m e i s cha r ac t er ize d by i n testi n al po l yp s a nd a n i n crease d r isk of c o l or e c t a l and b r eas t cance rs . T h is rare s ynd r o me is du e t o i nh erite d m u tati ons i n t he S T K 1 1 gene. A f fecte d w o me n als o h a v e a n i n crease d ri sk of ov a r ia n sex co r d–s tr o m a l t u m o rs wit h a nnu lar t ubu les a nd a d e no ma mali gnu m o f t he ce r v i x. Li-Fra u me n i s ynd r o me is ca u se d by i nh erite d m u tati ons i n t he TP 53 gene, a nd carriers are p re d is po se d t o a nu m b er o f t yp es of cance r s i nc l ud i ng sa r co mas a nd b reast ca n ce r . T h e ris k o f ov ari an ca n ce r i s i nc r eased as we ll , bu t is no t a maj o r ca u se o f ca n cer i n t h ese f amilies . Cowden synd r o m e i s du e t o g ermli n e PTEN m u tati on s a nd i n c r ease s t he ri sk o f seve r a l mali gn a n cies i n cl ud i ng b reast , t hy r o i d, m u c o c utaneous, and endo m e trial ca n cers . Fi n all y , small cell carci no ma o f t h e ov a r y , hype r ca l ce mi c t yp e , is du e t o m u tati on s i n t h e S MARCA 4 g e n e . Th ese h i gh l y l e t ha l ova ri an c a n cers o cc u r at a v er y young a g e (me d ia n 24 y ea r s ) a nd p r esen t d i f fi cu lt cha lle ng es relate d t o timi ng o f RRSO . T h ere a r e no w ell - a ccep t ed ev i dence - ba se d gu i d eli n es f o r earl y d etecti on a nd pr e v e n ti on o f gyneco l og i c can cers i n t h ese v er y rare h ere d itar y ca n cer

GYNECOLOGIC CANC E R RISK IN V E R Y RARE HE REDI T A R Y CANC E R SYNDROMES

nan nan

s yndro m es. An awa r eness o f th e ris k a nd n at u ral h ist o r y o f gyn ec o l og ic ca n ce r s i n t hese f a mili es p r ov i d es a b asis f o r c oun seli ng i nd i v i du al p atie nts.

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Gene Carriers

nan nan

Gene Carriers

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Gene Carriers

nan nan

Th e M E N t ype 2 synd r o m es i n cl ud e MEN 2 A , MEN 2 B , a nd familial ( n o n -M EN) medu ll a r y t hy r o i d ca r cino ma (FMTC) . T h ese are a u t o s o mal do mi n a n t i nhe rit ed synd r o m e s ca u se d by g ermli n e m u tati on s i n t h e RET pro t o-oncogene. T he ir ha llm ark is t h e d e v el op me n t o f m u ltif o cal b ilater al me du llar y t hy r o i d ca r c i no m a ( MTC) ass o ciate d wit h C-cell hyp er p lasia . M T Cs ari se fr o m t he t hy r o i d C-cells , als o calle d p araf o llic u lar cells . C-c ells sec r ete t he ho rm one ca l c it on i n, a s p ecific t u m o r mar k er f o r MTC . A sl ow - grow i ng t u m o r i n m os t cases, MTC ca u ses si gn ifica n t m o r b i d it y a nd d e ath i n p atie n t s w it h uncon tr o ll ed lo cal o r metastatic s p rea d. La r g e t u m o r bu r den is ass o ci a t ed w it h d i a rr hea and fl u s h i ng. I n t h e MEN 2 s ynd r o mes , t h ere is alm o st c o m p l e t e pene tr ance o f MTC . Ot h er feat u res are v aria b l y e xp res sed, w it h i n c o m p l e t e pene tr ance (s u mmarize d i n . In ME N 2A, a ll pa ti en t s dev el op MTC . A pp r ox imatel y 42 % o f affect ed p atie n ts al so deve l op pheoch r o m o c y t o mas , ass o ciate d wit h a d re n al me du llar y hype r p l as i a. Hype rparat hy r o i d ism d e v el op s i n 10 % t o 35 % .

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Gene Carriers

nan nan

C u ta n e ous li chen a m y l o i dos i s a nd Hirsc h s p r ung ’ s d isease are i n fre qu e n tl y ass o ciate d w it h M E N 2A M EN 2B appea r s t o be t he m o st a gg ressi v e f o rm o f h ere d itar y MTC . I n M EN 2B, M T C deve l ops i n al l p atie n ts at a v er y young a g e (i n fa n c y ) . A ll a f f ecte d i nd i v i dua l s deve l op n e u ral g a ng li o mas , p artic u larl y i n t h e m u c o s a of t h e d i ges ti ve tr ac t , con j unc ti v a , li p s , a nd t ongu e; 40 % t o 50 % d e v el op ph e o c hro m ocy t o m as. P a ti en t s wit h MEN 2 B ma y als o h a v e me g ac o l on, s k eletal abno rm a liti es, and m a r k e d l y e n lar g e d p eri ph eral n er v es . T h e y d o no t d e ve l op hype r pa r a t hy r o i di sm . FM T C i s cha r ac t e ri zed by d e v el op me n t o f MTC i n t h e a b se n ce o f a ny o t h e r e ndoc ri nopa t h i es. M T C i n t h ese p atie n ts h as a m o re i ndo le n t cli n i cal c our se . So m e i nd i v i dua l s w it h FMTC ma y n e v er ma n ifest cli n ical e v i d en ce ( i . e ., s ymp t o m s o r a l u m p i n t h e n ec k ) , alt hough b i o c h emical testi ng a nd h ist o l og i c eva l ua ti on o f t he t hy r o i d d em on strates MTC .

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

RET Genotype-Phenotype Cor r elations

nan nan

RET Genotype-Phenotype Cor r elations

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

RET Genotype-Phenotype Cor r elations

nan nan

M u tati ons i n t he RET p r o t o - on c og e n e are res pon si b le f o r MEN 2 A , ME N 2 B , a nd FM T C T h i s gene e n c od es a tra n smem b ra n e t y r o si n e k i n ase pro tei n T he m u t a ti ons t ha t ca u se t h e MEN 2 s ynd r o mes are acti v ati ng g ai n-of- f unc ti on m u t a ti ons a f fecti ng c on stit u ti v e acti v ati on o f t h e p r o tei n. Th is is unusua l a m ong he r ed i t ar y ca n cer s ynd r o mes , w h ic h are u s u all y ca u se d by l oss - o f-f unc ti on m u tati on s i n t h e p re d is po siti on g e n e (e .g., f amilial po l ypos i s, BR C A 1 and 2 , von Hi pp el-Li nd a u, a nd MEN 1 ) . M o r e t h a n 30 mi ssense m u t a ti ons hav e b ee n d escri b e d i n p atie n ts a f fecte d by t he M EN 2 synd r o m es ) .

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

RET Genotype-Phenotype Cor r elations

nan nan

Th e r e i s a r e l a ti onsh i p be t w ee n t h e t yp e o f i nh erite d RET m u tati on a nd pr ese n tati on o f M T C. T he m o st v ir u le n t f o rm is see n i n p atie n ts wit h M EN 2 B . Th es e pa ti en t s m os t co m mon l y h a v e a g ermli n e m u tati on i n c odon 918 of RE T ( A T G - >ACG ) , a lt hough o t h er m u tati on s h a v e b ee n d escri b e d ( c odon 883 and 922 ) . As no t ed p re v i ou sl y , MTC i n MEN 2 B h as a n e x t r eme ly ea rl y age o f onse t (i n fa n c y ) . Des p ite its d isti n cti v e cli n ical a pp ea r a nce and assoc i a t ed gas tr o i n testi n al d iffic u lties , t h e d isease is o ft en no t d ete c t ed un til t he pa ti en t d e v el op s a n ec k mass . Metastatic s p rea d is u s u all y p r esen t a t t he tim e o f i n itial treatme n t , a nd calcit on i n le v els o fte n r emai n e l eva t ed pos t ope r a ti ve l y . M TC has a va ri ab l e cou r s e i n p atie n ts wit h MEN 2 A , similar t o t h at o f s por a d ic M T C. Codon 634 and 618 m u tati on s are t h e m o st c o mm on RET m u tati ons assoc i a t ed w it h M EN 2 A , alt hough m u tati on s at o t h er c odon s a r e als o ob s e r ved ( see . S o me p atie n ts do e x tremel y well f o r ma ny

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

nan nan

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

nan nan

G e n etic counse li ng and i n f o rme d c on se n t s hou l d b e ob tai n e d p ri o r t o g e n etic tes ti ng. S pec ifi c i ssue s t h at s hou l d b e c ov ere d i n g e n etic c oun sel ing sessi on s i nc l ude exp l a i n i ng the p atter n s o f h erita b ilit y , li k eli hood o f e xpr essi on o f d i f f e r en t t u m o rs , t h eir p re v e n ti on a nd treatme n t , i n s u ra b ili t y , nonp ate rn it y , su r v i vo r gu ilt , a n d o t h ers . I t h a s been shown t ha t RET m u tati on carriers ma y h ar bo r f o ci o f MTC in t h e t hyro i d g l and, even when calcit on i n le v els are no rmal . W h ile t h e a ge of on set and r a t e o f d i sease p r og ressi on ma y d i f fe r , t h e lifetime p e n etra n c e of M T C i s nea r 100 % i n ca rri e rs o f RET m u tati on s ass o ciate d wit h ME N 2 s yndro m es. A t-ri sk i nd i v i dua ls w ho are f ound t o h a v e i nh erite d a RET gene m u tati on a r e t he r e f o r e cand i d ates f o r t hy r o i d ect o m y , re g ar d less o f t h eir p lasma ca l c it on i n l eve l s. Th e bes t op ti on f o r p r event i on o f MTC i n RET m u tati on carriers is c o m p let e su r g i ca l r esec ti on p ri o r t o mali gn a n t tra n sf o rmati on. Pr ophy la ctic t hyro i d ect o m y p ri o r t o t he dev el op me n t o f MTC is t h e go al i n t h ese p atie n ts . A nu m be r o f s t ud i es h a v e d em on strate d im p r ov e d b i o c h emical c ur e r at es and / o r dec r eased r e c u rre n ce rates fr o m earl y t hy r o i d ect o m y ,

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

nan nan

s hou l d b e gu i ded by ca l c it on i n le v els a nd cli n ical feat u res o f t h e p atie n t and k i ndr e d. Un til r ecen tl y , so m e g r oup s rec o mme nd e d t o tal t hy r o i d ect o m y wit h ce n t r al neck l y m ph node d i ss ecti on a nd t o tal p arat hy r o i d ect o m y wit h a u t o t r a nsp l an t a ti on f o r a ll RET m u tati on carriers . Rece n t st ud ies a nd p e r s on al expe ri ence, howeve r , h a v e d em on strate d a n e x tremel y l o w li k eli hood o f noda l m e t as t ase s i n p atie n ts wit h MEN 2 A o r FMTC younge r t h a n 8 yea r s o f age, and i n pa tie n ts wit h a no rmal calcit on i n le v el . O u r c urr e n t s tr a t egy i s t o l eave t he p arat hy r o i d i n sit u i n t h ese p atie n ts , if po ssi b le O ft en, howeve r , t h e d esire d c o m p lete rem ov al o f t hy r o i d tiss ue r es u lts i n co m p r o mi se o f pa r athy r o i d b l ood s upp l y . I n t h ese sit u ati on s , a u t o t r a nsp l an t a ti on o f devasc ularize d p arat hy r o i d is re qu ire d. W e r ou ti nely r em ov e and au t o tr ansp l an t t h e p arat hy r o i d if a ce n tral nod e d issecti on is don e . In pa r a t hy r o i d au t o tr ansp la n tati on, p arat hy r o i d g la nd s are slice d in to 1 mm × 3 mm fr ag m en t s and au t o tra n s p la n te d i n t o i nd i v i du al m u scle po c k ets i n t he m usc l e o f t he nondo mi n a n t f o rearm i n p atie n ts wit h MEN 2A, or i n t he s t e r noc l e i do m as t o i d m u scle i n p atie n ts wit h FMTC o r ME N 2 B . P atie n t s a r e m a i n t a i ned on calci u m a nd v itami n D s upp leme n tati on fo r 4 t o 8 weeks pos t ope r a ti ve l y . In a recen t se ri es o f t hy r o i d ect o mies p erf o rme d i n 50 i nd i v i du als wit h M EN 2A (i den tifi ed by gene tic scree n i ng ) , t o tal t hy r o i d ect o m y a nd ce n tr al nod e d iss ec ti on w it h pa r a t hy r o i d ect o m y a nd p arat hy r o i d a u t og rafti ng w e r e p e rfor me d i n a ll pa ti en t s ) . All a u t og rafts f un cti on e d, bu t t h r ee p atie n ts requ ir ed supp l e m en tal calci u m . T h e p erce n ta g e o f i nd i v i du als r e qu i r i ng ca l c i u m supp l e m en tati on f o ll o wi ng p arat hy r o i d ect o m y wit h p a r at hyro i d au t og r a fti ng r epo rte d l y ra ng es fr o m 0 % t o 18 % . Pa r at hyro i dec t o m y shou l d be p erf o rme d i n all p atie n ts s ho wi ng g r o ss p a r at hyro i d en l a r ge m en t o r b i o c h emical e v i d e n ce o f p arat hy r o i d d isease at time of su r ge r y . T he ope r a ti ng s u r g e on s hou l d h a v e e xp ertise i n pr ese rv a t i on o f pa r a t hy r o i d f un cti on. It is im po rta n t t h at t h e s u r g e on p e rfor m ing an ope r a ti ve p r oc e du re f o r MTC b e familiar wit h t h e tec hn i ques d esc r i b e d he r e. If no t , t he pa t i e n t s hou l d b e referre d t o a ce n ter w h ere t h e se pro ce du r es a r e r ou ti ne l y pe rf o rme d.

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

nan nan

S o m e pa ti en t s w it h M E N 2 will b e f ound t o h a v e ele v ate d calcit on i n le v els p ri o r t o t hy r o i dec t o m y . T h is is u s u all y ass o ciate d wit h me du llar y t hyro i d ca r c i no m a o r C - ce ll hyp er p lasia i n t h e g la nd, a nd ma y b e ass o ci ated w it h l y m ph node m e t as t ases. M u c h h as b ee n writte n a bou t t h e c o rrelati on b et w ee n p r eope r a ti ve ca l c it on i n le v els a nd e x te n t o f nod al i nvo l v eme n t . I t h as b ee n sugges t ed t ha t p r eop erati v e calcit on i n le v el ma y gu i d e t h e e x ten t of nod e d i ssec ti on. I n a s t udy o f 300 E u r op ea n p atie n ts wit h MTC , nod e metasta ses we r e no t i den tifi ed w h e n t h e p re op erati v e b asal calcit on i n le vel w as < 20 pg /ml . I nvo l ve m en t o f nod al g r oup s was c o rrelate d wit h b asal calcit on i n l eve l as f o ll ows : i p silateral ce n tral a nd lateral n ec k nod es ( b as al calcit on i n >20 pg /ml) , con tr a lateral ce n tral nod es ( b asal calcit on i n >50 pg /ml ), c on tr a l a t e r a l l a t e r a l n ec k nod es ( b asal calcit on i n >200 pg /ml) , a nd me d iastin a l nodes ( basa l ca l c it on i n >500 pg /ml) . Base d upon t h ese fi nd i ngs, t h is group ( who a l so w r o t e t h e E u r op ea n gu i d eli n es) rec o mme nd s t hyro i d ect o m y on l y if basa l ca lcit on i n is <20 pg /ml , i p silateral ce n tral a nd late r al neck d i ssec ti on if t he c alcit on i n is 20 t o 50 pg /ml , a nd c on tralater al ce n t r al neck d i ssec ti on if t he b asal calcit on i n is 50 t o 200 pg /ml , wit h t he a dd iti on o f con tr a l a t e r a l l a t e ral n ec k d issecti on if t h e calcit on i n is 200 t o 500 pg /ml . Mos t expe rt s ag r e e t h at ster no t o m y wit h me d iasti n al n ec k d issecti on shou l d be r ese r ved f o r p atie n ts wit h ima g e e v i d e n ce o f me d iastin a l d i sease. I n con tr as t , m o st N o rt h America n s u r g e on s rel y h ea vily

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Risk-Reducing Thy r oidectomy in RET Mutation Carriers

nan nan

upon pr e ope r a ti ve u ltr asound ima g i ng t o ma p t h e e x te n t o f nod al i nvo l v em en t and de t e rmi ne ex te n t o f s u r g er y b ase d upon calcit on i n a nd ima g i ng r esu lt s ,

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Follow-up

nan nan

Follow-up

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Follow-up

nan nan

F o ll ow i ng t hy r o i dec t o m y , t hy r o i d ho rm on e re p laceme n t is re qu ire d f o r l i f e. Patie n ts m ay need seve r a l we e k s o f o ral calci u m a nd v itami n D un til p a r at hyro i d f unc ti on r ecove r s. I n termitte n t calcit on i n testi ng ma y b e done t o m on itor f o r pe r s i s t en t o r r e c u rre n t MTC . T h e im po rta n ce o f re gu lar m on it oring o f pa ti en t s ’ co m pl ia n ce wit h t hy r o i d me d icati on f o ll o wi ng t hyro i d ect o m y shou l d no t be und erestimate d. C h il d re n a nd tee n a g ers are fr e qu e n tl y nonco m p li an t , and t h is ca n b e d etermi n e d by r ou ti n e meas ur em en t o f t hy r o i d - s timulati ng ho rm on e le v els . C on ti nu e d non c o m p li ance can r esu lt i n g r o wt h p r ob lems . Occasi on all y , l o cal hu ma n se rv ices agenc i es m ay need t o b e i nvo l v e d i n p artic u larl y d i f fic u lt cases . Th e t e rm “b i oche mi ca l cur e” is u se d t o refer t o p atie n ts wit h no rmal calcit on i n l eve l s a ft e r su r ge r y f o r MTC . C o m p lete po st op erati v e nor mali za ti on o f ca l c it on i n ha s b ee n ass o ciate d wit h d ecrease d l ong -ter m r is k of M T C r ecu rr ence, t hough t h e e v i d e n ce is less clear f o r a s u r v i v al b e n e f it . A pe r s i s t en t o r r ecu rr en t ele v ati on i n calcit on i n i nd icates resi dual o r r ec urr e n t M T C and wa rr an t s add iti on al i nv esti g ati on by ima g i ng. H o we ve r , as m o st M T C has a f a irl y i ndo le n t c ou rse , p atie n ts wit h b i o c h emical e v i d e n ce o f r ecu rr en t d i sease ma y no t h a v e c o r o llar y ima g i ng fi nd i ng s f o r s o me ti me.

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Conclusions

nan nan

Id e n ti f icati on o f RET gene m u tati on s i n i nd i v i du als at ris k f o r d e v el op i ng h e r e d ita ry f o rm s o f M T C has sim p lifie d ma n a g eme n t , e xp a nd i ng t h e sc ope of i nd ic a ti ons f o r su r g i ca l i n ter v e n ti on. Patie n ts w ho carr y t h is m u tati on can b e o f f e r e d ope r a ti ve tr ea tm en t at a v er y young a g e , hop ef u ll y b ef o re t h e ca n ce r h a s deve l oped o r sp r ead, a nd t ho se i d e n tifie d as no t h a v i ng t h e m u tati on a r e spa r ed f u rt he r g e n etic a nd b i o c h emical scree n i ng. T h is

MU L TI P LE E ND O CRINE NEOPL A SIA TY P E 2

Conclusions

nan nan

ac h ie v em en t m a r ks a new pa ra d i g m i n s u r g er y : t h e i nd icati on t h at a n op e r ati on be pe rf o rm ed based on t h e res u lts o f a g e n etic test . As i n t h e d ecisi on t o pe rf o rm any su r g ical p r o ce du re , metic u l ou s p re p arati on a nd d etaile d d i scuss i on w it h pa ti en t a nd famil y m u st p rece d e t h e fi n al r ec o mm enda ti on. It i s a l so imp o rta n t t h at t h e p atie n t a nd famil y b e i nvo l ved i n pr e ope r a ti ve d i scuss i ons wi t h g e n etic c oun sel o rs . P o st op erati v e f o ll ow - up for c o m p li ance w it h t hy r o i d me d icati on is im po rta n t , es p eciall y i n c h il dr e n and t eenage r s who a re still g r o wi ng a nd d e v el op i ng i n t o a du lts .