Evidence-based clinical practice parameter guidelines for the treatment of patients with metastatic brain tumors Steven N.

Kalkanis and Mark A. Linskey 2012 Introduction Why clinical guidelines are desirable and i !ortant" #ro!erly understood and e !loyed$ evidence%based edicine &'(M) is a tool o* considerable value *or edicine and neuro% oncology. It !rovides a secure$ scienti*ically%de*ensible base *or clinical !ractice and !ractice i !rove ent. +o,ever$ !ursued on an individual case%by%case basis$ in !urest *or $ it can be ine**icient and ti e consu ing$ !articularly *or health !roviders ,ith e-tre ely busy clinical !ractices. .linical guidelines based on the best evidence available$ develo!ed and regularly u!dated by sub/ect atter e-!erts$ *ocusing on co on and i !ortant clinical scenarios and 0uestions$ have the !otential to be very desirable$ use*ul$ and e**icient '(M tools *or o!ti i1ing !atient care. .linical !ractice !ara eter guidelines are de*ined as 2syste atically develo!ed state ents to assist !ractitioner and !atient decisions about a!!ro!riate health care *or s!eci*ic individual circu stances. An advantage o* utili1ing guidelines in clinical decision% aking over sole reliance on rando i1ed controlled trial &3.4) results$ is that they take !ro*essional e-!erience into account in an aggregate and ore syste atic anner$ rather than on an individual or ad hoc basis. Not only are ore 5e-!erts6 involved in the consensus !rocess &diluting out outliers in o!inion)$ but$ in an evidence%based guidelines develo! ent !rocess$ the o!inions solicited are the e-!erts7 o!inions about the collected evidence in the literature$ rather than si !ly their o,n !ersonal o!inions regarding the sub/ect.
Multidisci!linary$ evidence%linked clinical !ractice !ara eter guidelines$ based on the ost rigorous evidence%based ethodology$ o**er the !otential o* reducing une-!lainable variation in clinical !ractice ,hile elevating the 0uality o* !atient care to the highest levels su!!orted by the best available$ and ost u!%to%date$ evidence. 4hey also have the !otential to clearly !oint out ,here critical evidence 5ga!s6 e-ist in areas i !ortant to clinical care that can then subse0uently be *illed by directed research !lanning and invest ent. 4he goal o* this guideline initiative is to o!ti i1e the care and outco e o* our !atients ,ith brain etastases$ by !roviding the ost ethodologically valid$ evidence%linked treat ent reco endations in a user%*riendly and co !rehensive anner$ *or real%,orld clinical scenarios encountered by clinicians and !atients every day. 4he healthcare !olicy i !lications o* clinical !ractice !ara eter guidelines are very real and deserve the care*ul attention o* both individual !ractitioners and our national edical !ro*essional organi1ations. Legislation e**orts currently active in Washington include language *ocusing on develo! ent and inclusion o* 5a!!ro!riateness criteria6 as a eans o* restricting edical care and reducing edical costs. 4hey also include language *ocusing on the develo! ent and *unding o* co !arative e**ectiveness research analy1ing clinical e**ectiveness$ and not /ust cost e**ectiveness. 'ach o* these e**orts ,ill likely lead to a search *or the best available clinical !ractice guidelines in key !ublic health i !act areas *or the !ur!ose o* i !roving value *or every healthcare dollar s!ent$ as ,ell as reducing cost through !ractice restriction. It is in our !atients7 interest$ as ,ell as our o,n as !atient

advocates$ to ensure the availability o* the highest 0uality guidelines based on a rigorous ethodology$ ,here strength o* reco endations cannot e-ceed the strength o* available evidence.

Why brain metastases are an important area for clinical guideline development
Secondary brain tu ors$ or brain etastases$ are 89: ti es ore co on in incidence than !ri ary brain tu ors. ;urther ore$ by de*inition$ etastatic brain tu ors i !ly !ri ary cancers that can s!an the *ull ga ut o* organ%based subs!ecialty clinical !ractice in edicine. 4hus$ *ro a !ublic health i !act$ evidence%linked clinical !ractice !ara eter guidelines regarding the care o* !atients ,ith etastatic brain tu ors are likely to !ositively i !act ore !atients$ as ,ell as ore edical !ractitioners$ than any other !otential to!ic ,ithin neuro%oncology.
How can clinicians and patients best navigate through the myriad of treatment decision pathways for brain metastases?

According to the 200< A erican .ancer Society 3egistry$ a!!ro-i ately 1.8 illion A ericans are diagnosed ,ith cancer every year and u! to 80= o* these !atients>over a hal* illion !eo!le annually>,ill go onto develo! one or ore brain etastases. While lung and breast are the ost co on tu or ty!es$ any alignancies etastasi1e to the brain. 4reat ent decisions ust be individuali1ed based on a co !le- array o* both !atient% s!eci*ic and tu or%s!eci*ic characteristics$ es!ecially since the nu ber o* thera!eutic o!tions has gro,n considerably over the !ast t,o decades. A !aradig shi*t has occurred in the evolution o* ho, ,e treat !atients ,ith brain etastases. No longer relegated to the real o* !alliation ,ith an e-!ectation o* a ra!id neurological decline and inevitable neurological de ise$ !atients ,ith brain etastases no, have a yriad o* aggressive treat ent o!tions available to the $ resulting in a longer li*e e-!ectancy and better 0uality o* li*e. With the use o* arkedly i !roved local control easures$ !atients are no, o*ten /ust as likely to succu b *ro their syste ic disease$ than *ro their brain tu or&s). Whole brain radiation thera!y &W(34) has been the ainstay o* etastatic brain tu or thera!y *or decades through the id%1??0s. +o,ever$ ore recent data has highlighted the !otential bene*it o* ore aggressive local control easures involving surgical resection and stereotactic radiosurgery &S3S) in addition to W(34. 'ven ore recently$ S3S alone$ surgical resection and S3S$ che othera!y$ and several cutting%edge investigational ad/uvant thera!ies have co e under consideration. 4he ty!ical brain etastasis !atient no, encounters not only a general edical oncologist and a radiation oncologist$ but also a neurosurgeon$ and a neuro%oncologist.

Guidelines for creating guidelines

4he ulti ate validity o* any guideline is critically related to three key *actors@ &1) the co !osition o* the guideline !anel and its !rocess$ &2) the identi*ication and synthesis o* the evidence$ and &A) the ethod o* guideline construction a!!lied. 4he !anel co !osition is crucial$ both *or ulti ate acce!tance o* the guidelines by !racticing !hysicians and *or its critical in*luence on the reco endation ste! o* guideline construction. Success*ul introduction o* a guideline re0uires that all key disci!lines contribute to its develo! ent to

ensure o,nershi! and su!!ort. While s!onsored by the A erican Association o* Neurological Surgeons &AANS)$ the .ongress o* Neurological Surgeons &.NS)$ and the AANSB.NS Coint 4u or Section$ this guideline initiative ,as !ro%actively designed to be as inclusive o* other related disci!lines as !ossible to a-i i1e its 0uality$ acce!tance$ and !otential i !act. In addition to !ro inent neurosurgeons involved in surgical neuro% oncology and stereotactic radiosurgery$ the ultidisci!linary ,riting !anel includes nationally recogni1ed e-!erts *ro radiation oncology$ edical oncology$ and neuro% oncology. In order to a-i i1e the 0uality o* the identi*ication and synthesis o* evidence as ,ell as the s!eed and e**iciency o* guideline develo! ent$ the three organi1ations s!onsoring this initiative contracted ,ith McMaster Dniversity to *acilitate the !rocess over an antici!ated t,elve onth ti etable. 4he McMaster 'vidence%(ased #ractice .enter &'#.) is one o* 1: '#.s *ederally *unded through grants *ro the Agency *or +ealthcare 3esearch and Euality &A+3E) to assist in !ro oting 0uality o* healthcare$ reducing its cost$ i !roving !atient sa*ety$ decreasing edical errors$ and broadening access to essential services by su!!orting outco es studies$ and i !le enting their *indings through the disse ination o* clinical guidelines in the D.S. '-tre ely e-!ert in '(M techni0ues$ and ,ith an e-!erienced sta** and asset in*rastructure in !lace$ they have been instru ental in hel!ing the author grou! e-!edite their ,ork at the highest !ossible 0uality level$ ,ithout any di inution o* thoroughness or scienti*ic rigor. 4he choice o* a rigorous evidence%linked reco endation ethodology over an in*or al or *or al consensus ethodology ,as !ur!ose*ully chosen to a-i i1e rigor o* the result and !revent over%ste!!ing the strength o* available evidence. .onsensus guidelines can !roduce very valid and use*ul conclusions$ ho,ever$ one o* their ain ,eaknesses is that they o*ten lead to reco endations even in areas ,here there is insu**icient strength o* evidence to reco end one a!!roach over another. 4ruly evidence%linked guidelines are i !ortant *or !ointing out reco endations based on !ertinent evidence$ but they have an even ore i !ortant *unction in allo,ing and !reserving !rovider autono y and *le-ibility in areas ,here insu**icient evidence or strength o* evidence e-ists to reco end standardi1ation. 4he *ear o* 22cook book77 edicine resulting *ro the a!!lication o* guidelines to clinical !ractice is best itigated by adherence to strict evidence%linked ethodology.

How this process is different

Not all guidelines are e0uivalent in 0uality. According to Wool*$ there are three ain ethods o* guideline develo! ent>in*or al consensus$ *or al consensus$ and evidence% linked develo! ent. ;ro the stand!oint o* evidence based edicine &'(M)$ only the latter has evidentiary status *or '(M decision% aking. Indeed$ the D.S. Institute o* Medicine ho!es to eventually restrict the use o* the ter 22guideline77 to syste atically develo!ed advisory state ents created according to validated ethodology. So e consider consensus guidelines as intellectually sus!ect by re*lecting e-!ert o!inion$ ,hich ,hen !ro ulgated as a 22guideline$77 can *or ali1e unsound !ractice. Without strict adherence to syste atic and validated ethodology$ !anelists ay be !ooling ignorance as uch as distilling ,isdo . So e guidelines are o* 0uestionable 0uality and there have been calls *or guidelines on ho, to devise guidelines.

4he D.S. National Fuidelines .learinghouse &NF.) Ghtt!@BB,,,.guideline.govH currently includes guidelines that have been *or ed through e-!ert consensus alongside those based in syste atic evidence%based ethodology. It also includes guidelines that have been created by s!ecial interest and advocacy grou!s$ subs!ecialty organi1ations$ insurance co !anies$ !rivate consulting *ir s$ cross%re!resentative !anels designed to include re!resentatives *ro all !otential stakeholders$ and 'vidence%(ased #ractice .enters &'#.s). Many o* these guidelines con*lict ,ith one another$ and there is currently no eans o* resolving or ad/udicating these con*licts other than individual !roviders or oversight organi1ations aking their o,n decision&s) as to ,hich should take a !osition o* su!re acy or authority. (y clearly outlining our search !rocess as *acilitated by the McMaster Dniversity '#.$ !ublishing our evidence tables$ identi*ying the evidence and their rated strength$ !roviding the linkage bet,een identi*ied evidence and each !ublished reco endation$ as ,ell as !ublishing the rationale *or the resultant strength o* reco endation$ this guideline e**ort re!resents the ost rigorous$ and trans!arently veri*iable$ clinical !ractice !ara eter guidelines e**ort *or etastatic brain tu ors yet achieved. ;urther ore$ this e**ort is ore u!%to%date at ti e o* !ublication than any !revious guidelines e**orts$ in large !art due to the assistance o* the McMaster Dniversity '#. in *acilitating a 1A onth start%co !letion ti eline. Fiven that ost guideline !ro/ects take over three years to co !lete$ and have an average evidence obsolescence shel*%li*e o* a!!ro-i ately *ive to seven years$ our e-!edited ti eline ,ill ho!e*ully lead to a-i al clinical i !act *or a longer duration than !revious e**orts. Lastly$ ,e strongly believe that any set o* co !rehensive brain etastasis guidelines should not erely serve as a re*lection o* the best currently%available evidence$ but should also shine a light on critical unans,ered 0uestions to develo! ne, !ath,ays *or *uture treat ents. We also designed these guidelines to su!!ort the acade ic ission o* our colleagues in institutions around the country ,ho are seeking to discover the ne-t *rontiers in neuro%oncology. 4o these ends$ every cha!ter$ ,henever available$ lists i !ortant needed areas o* study and *uture directions *or various clinical scenarios$ and also outlines a current list o* o!en clinical trials co !aring one brain etastasis treat ent odality to another>including treat ents in radiothera!y$ stereotactic radiosurgery$ surgery and che othera!y as ,ell as treat ents utili1ing novel$ e erging agents and co bination thera!ies. .linicians are encouraged to use these listings to su!!ort and enroll their !atients in these i !ortant ongoing studies so that ,hen these guidelines are u!dated in a *e, years$ uch ore !o,er*ul evidence ay e-ist *or ado!ting one treat ent regi en over another.

Ranking clinical treatment scenarios by levels of recommendation

As described in ore detail in the *ollo,ing ethodology cha!ter$ every clinical treat ent scenario involving brain etastases ,as highlighted and ranked by a level o* reco endation$ ,ith Level 1 being the highest$ and Level A the lo,est$ ,ith so eti es no reco endations being ade de!ending on the 0uantity and 0uality o* the evidence. 3igorous and lively debate ensued bet,een all o* the authors$ but ulti ately every author on the ,riting !anel agreed to all o* the ulti ate reco endations a*ter a care*ul revie, o* the evidence itsel* and the strength o* the evidence. 4he !anel7s strict adherence to the t,o% ste! syste atic revie, !rocess$ in collaboration ,ith our McMaster '#. !artners$ highlights

a critically i !ortant and uni0ue *eature o* this e**ort. As ight be e-!ected$ given its ra!idly e erging role in the treat ent o* brain etastases over the !ast decade$ the S3S reco endations engendered the ost s!irited discussions a ongst our ultidisci!linary !anel. Nonetheless$ each reco endation ,as care*ully constructed to stay *ully ,ithin the con*ines o* the !o,er o* the evidence in a !rocess *ully su!!orted and endorsed by all e bers o* the !anel. With a clear recognition o* both their li itations and !ro ise$ these clinical treat ent scenarios and reco endations have been organi1ed into the *ollo,ing cha!ters@ 1. 3adiation thera!y in ne,ly%diagnosed brain etastases 2. Surgical resection in ne,ly%diagnosed brain etastases A. Stereotactic radiosurgery in ne,ly%diagnosed brain 8. .he othera!y in ne,ly%diagnosed brain :. 3e%treat ent etastases etastases etastases

odalities *or recurrent andBor !rogressive brain etastases

I. 4he role o* !ro!hylactic anticonvulsants in brain J. 4he role o* steroid thera!y in brain etastases

<. Novel and investigational thera!ies *or brain

etastases

Addition o* I unothera!y #rolongs Survival in Kidney .ancer Kosia .hustecka 201A

Adding the e-!eri ental i unothera!y AFS%00A &Argos 4hera!eutics) to standard targeted thera!y ,ith sunitinib &Sutent$ #*i1er) !rolonged e-!ected survival ti e in !atients ,ith advanced kidney cancer. 4his *inding co es *ro a s all single%grou! !hase 2 study o* !atients ,ith etastatic renal cell carcino a. 4he results ,ere !resented by Asi A in$ ML$ #hL$ codirector o* the Levine .ancer Institute in .harlotte$ North .arolina$ at the 201A Fenitourinary .ancers Sy !osiu &FD.S) in Mrlando$ ;lorida. All o* the 21 !atients had an un*avorable !rognosis. ;or !oor%risk !atients$ !redicted overall survival ,as around < onthsN *or inter ediate%risk !atients$ it ,as 22 onths. +o,ever$ ore hal* o* the !atients survived *or ore than A0 onths$ and one third are still alive a*ter 8 years or ore. 4his OstrikingO !rolongation o* survival has !ro !ted a larger !hase A study$ ,hich has already started enrolling !atients$ according to Argos 4hera!eutics. Fully ersonali!ed "mmunotherapy AFS%00A is !roduced by e-tracting essenger 3NA *ro a sa !le o* a !atientPs tu or &obtained at the ti e o* ne!hrecto y) and incor!orating it into the !atientPs dendritic cells &obtained during a single leuka!heresis !rocedure). 4his is a *ully !ersonali1ed i unothera!y$ Lr. A in told Medscape Medical News. It is di**erent *ro the !rostate cancer vaccine$ si!uleucel%4 & Provenge$ Lendreon)$ ,hich is O!ersonali1ed$ but only in !art$O he noted. ;or the !roduction o* si!uleucel% 4$ dendritic cells are collected *ro !atients$ but these cells are then !rogra ed ,ith a PgenericP !rostate cancer antigenN the sa e antigen is used in every !atient$ he e-!lained. In AFS%00A$ the dendritic cells o* each !atient are !rogra ed ,ith antigens *ro their o,n tu or$ he added.

O4he issue ,ith kidney cancer is that ,e have not identi*ied any a/or antigens$ unlike in elano a and !rostate cancer.... 4his is ,hy ,e need to use the !atientPs o,n tu or$O he said. According to Argos 4hera!eutics$ the tu or 3NA is used to O!rogra O the dendritic cells ,ith the entire disease%antigen re!ertoire to trigger a res!onse against the !atientPs s!eci*ic tu or. In the !hase 2 trial$ blood sa !les indicate that !atients have antitu or e ory 4 cells. 4here is a correlation bet,een overall survival and the nu ber o* these cells that are induced. rolongation of #urvival 4he !rolongation o* survival is not a co !lete sur!rise. O4his has been seen be*ore ,ith i uno odulation$O Lr. A in noted. So e o* kidney cancer !atients treated ,ith high%dose interleukin%2 are living *or 10 to 1: years. +o,ever$ because o* the to-ic events associated ,ith this thera!y$ it is only a!!licable to about 10= o* !atients$ he said. 4yrosine%kinase inhibitors such as sunitinib have Orevolutioni1ed the treat ent o* kidney cancerN no, everybody can get a drug treat ent$O he said. +o,ever$ although they do !rolong survival$ the res!onses are not durable. In this trial$ Lr. A in and colleagues have sho,n that adding i unothera!y to standard thera!y increases the durability o* the res!onse$ and AFS%00A is not associated ,ith any to-ic events$ other than in/ection%site reactions and erythe a$ he said. 4he researchers chose to co bine AFS%00A ,ith sunitinib because it also has so e i uno odulatory !ro!ertiesN it su!!resses 4 regulatory and yeloid su!!ressor cells. Mther tyrosine%kinase inhibitors used in the treat ent o* kidney cancer ight not be such a good atch. ;or instance$ sora*enib inhibits dendritic cell *unction$ Lr. A in noted$ so could inter*ere ,ith the echanis o* action o* AFS%00A. In this trial$ all !atients ,ere treated ,ith standard I%,eek cycles o* sunitinib. AFS% 00A ,as ad inistered once every A ,eeks$ *or : doses$ and then every 12 ,eeks until the disease !rogressed. Median !rogression%*ree survival ,as 11.2 onths and the *inal survival ,as A0.2 onths$ Lr. A in re!orted. edian overall

+o,ever$ ,hen the !atients ,ere subdivided according to baseline risk$ the 11 inter ediate%risk !atients had a edian !rogression%*ree survival o* 1?.8 onths and a edian overall survival o* A?.: onths. 4he 10 !oor%risk !atients had a edian !rogression%*ree survival o* :.< onths and a edian overall survival o* ?.1 onths. ;or co !arison$ Lr. A in noted that a !ivotal trial in ,hich sunitinib ,as used alone sho,ed that edian overall survival ,as :.A onths *or !oor%risk !atients and 20.J onths *or inter ediate%risk !atients. 4he addition o* i unothera!y to sunitinib led to a Onear doubling o* the e-!ected !rogression%*ree and overall survival *or un*avorable%risk sub/ects$O he concluded. $arger %rial &lready 'nderway 4he A erican Society o* .linical Mncology$ ,hich cos!onsored FD.S$ highlighted this abstract in its !ress aterials. Leonard Fo ella$ ML$ ;A.S$ a e ber o* the FD.S ne,s !lanning tea $ noted that such !rolonged survival is Overy encouraging$O but it ,ill need to be con*ir ed in larger nu ber o* !atients. A larger trial is already under,ay. It is e-!ected that the !hase A ALA#4 study$ a rando i1ed ulticenter o!en%label trial$ ,ill enroll 8:0 !atients$ ainly in the Dnited States. It ,ill co !are the i unothera!y !lus sunitinib ,ith sunitinib alone. 4he !lan is to ad inister AFS%00A in < doses over the initial 12 onths$ *ollo,ed by booster shots every A onths *or !atients ,ho are continuing to bene*it.