Adriana Dalea

February 19, 2014

DOS 711
Trade Article vs. Peer Reviewed Article
Part I Trade Journal Article Review
Trade articles are addressed to the general public and are inor!ally "ritten# Their topics
are o broad interest and they could be pertaining to ne" products, acti$ities or ne"s in a
certain area#%1& The inor!ation is gathered by the "riters or clinicians "or'ing in the
ield and in$ol$ed in that speciic !atter o interest#
(n this paper ( "ill briely su!!ari)e and discuss an interesting trade article presented in
the *adiology Today +ournal# The article is "ritten by Dan ,ar$ey and it is entitled
-roton Therapy.Scaling Do"n to Fit the /o!!unity Setting#
The article is presenting in a positi$e light the ad$ance!ents in creating ne" proton
centers in the 0nited States# The t"o co!panies that are discussed are -ro/ure and Still
*i$er Syste!s, but the ocus is !ostly on the -ro/ure -roton /enter, their business
!odel, and the ad$antages that are oered#%2&
2
There are also discussed the high costs or
building these centers, and the tendency o these costs to start to decrease due to the
inno$ati$e "ays that co!panies li'e -ro/ure use in !a'ing possible to create and start
the use o such a acility# The !a1or challenges are presented and the ad$ance!ents in
technology that "ere !ade until 2009, "hen the article "as "ritten#
The costs o building a ne" proton center can reach 2100,000,000, they need enor!ous
!agnets and cyclotrons, !ultiple treat!ent roo!s, and !ultiloor gantries# -ro/ure is
able to pro$ide the inancing o the pro1ect, besides the logistics and the technology# The
business !odel is to create a partnership "ith the hospital and the co!!unity# The
positi$e aspect is that -ro/ure "ill do all the "or' to ha$e the proton center inali)ed and
ready to be opened or business and the healthcare institution "ith its clinical sta "ill be
ocused to 1ust ta'e care o the patients# Another plus or the co!pany is that the sta
"ill beneit o a co!prehensi$e training in proton therapy, use o the e3uip!ent and
technology#
(n the article it is speciied that the high cost o building a proton center started to
gradually decrease due to the proprietary technology o this business !odel that "as
de$eloped#
( ound this article an interesting reading or the !edical dosi!etry proessionals because
it describes ho" the proton therapy acilities are created and their tendency o e4pansion
in the radiation oncology ield# The author !a'es a good point in raising the a"areness
or the readers regarding the radiation treat!ent "ith protons# One thing that the article is
lac'ing is the support or so!e o the state!ents !ade# For e4a!ple, it is !entioned that
the proton therapy has better outco!es than photon therapy, but it is not supported "ith
any data, or studies# 5ith the ne" inno$ations in radiation therapy "ith 6.rays, the ne"
technologies can help deli$er the dose $ery accurately and spare the ad1acent tissues "ith
the sa!e precision as protons# This is a disputable topic and it dependable o !any
actors#
References:
1# 7enards 8#, 5eege 9# Radiation Therapy and Medical Dosimetry Reading#
%-o"erpoint&# 7a /rosse, 5(: 05.7 9edical Dosi!etry -rogra!; 2014#
2# ,ar$ey D# -roton therapy . scaling do"n to it the co!!unity setting# Radiology Today#
2009;10<1=>:14# http:??"""#radiologytoday#net?archi$e?090709p14#sht!l # Accessed
February 19, 2014#
September 7, !!"
Proton T#erap$ % Scalin& 'own to (it t#e )ommunit$ Settin&
*$ 'an +arve$
Radiology Today
,ol. -! .o. -/ P. -0
5hile proton bea! therapy has ad$anced radiation treat!ent or
nu!erous cancers, its cost to deli$er tends to restrict its application to
large research centers# -roton therapy acilities typically re3uire
enor!ous cyclotrons and !agnets, !ultiple treat!ent roo!s, and
to"ering, !ultiloor gantries that "eigh at least 100 tons# Total cost or a
treat!ent center can easily top 2100 !illion#
@ut those costs are starting to co!e do"n# Technology ad$ances coupled "ith inno$ati$e
business !odels are shrin'ing the si)e and cost o proton therapy and enabling its initial
penetration into co!!unity hospital and pri$ate practice settings, !a'ing the treat!ent a$ailable
to !ore physicians and patients in settings that pre$iously see!ed i!probable#
For 5illia! /# Aoad, 9D, ounder o the eight.!e!ber, O'laho!a.based *adiation 9edicine
Associates pri$ate practice physicians group, itBs al!ost too good to belie$e# C-roton therapy is
so!ething "e once only appreciated through !edical literature,D he says# C5e ne$er drea!ed
"eBd set oot in a center that "ould pro$ide us access to treat!ent technology#D
5hen the acility that Aoad directs, the -ro/ure -roton Therapy /enter in O'laho!a /ity,
opened +uly 1, it beca!e one o only si4 proton therapy centers in the 0nited States# (t 1oins a
select group that includes the 9id"est -roton *adiotherapy (nstitute at (ndiana 0ni$ersity, the
Francis ,# @urr -roton Therapy /enter at 9assachusetts Aeneral ,ospital in @oston, the -roton
Therapy /enter at 9# D# Anderson /ancer /enter at the 0ni$ersity o Te4as in ,ouston, 7o!a
7inda 0ni$ersity 9edical /enter in /aliornia, and the 0ni$ersity o Florida -roton Therapy
(nstitute in +ac'son$ille#
0nli'e the i$e others, the O'laho!a center operates at the co!!unity le$el# (t has ta'en proton
therapy ro! the research setting and !ade it a$ailable to patients "ho once "ould ha$e had to
tra$el ar to recei$e treat!ent#
)ompre#ensive *usiness 1odel
Established in 200F by +ohn /a!eron, -hD, -ro/ure de$eloped a turn'ey business !odel that
co$ers proton therapy acility de$elop!ent Cro! A to G,D as the ounder says# C5e do !ore
than 1ust sell or lease e3uip!ent# Our business !odel in$ol$es inancing the operation, pro$iding
building design, super$ising the construction, as "ell as e3uip!ent installation and acility
!anage!ent,D says /a!eron, "ho pioneered particle physics at (ndiana 0ni$ersity and helped
create the 9id"est -roton *adiotherapy (nstitute#
C5e could ne$er ha$e acco!plished this on our o"n,D says Aoad, !edical director o the
=0,000.s3uare.oot center that includes our treat!ent roo!s and a co!pact cyclotron# CThe
co!panyBs co!prehensi$e business !odel lea$es patient treat!ent up to the physicians# -ro/ure
ta'es care o e$erything else#D
-ro/ureBs approach reduces capital e4penditure and operating costs# (ts building design has a
!uch s!aller ootprint than the original proton therapy acilities, and the co!pany says its
e3uip!ent costs 20H to 40H less due to its proprietary technology and relationships "ith
e3uip!ent pro$iders# For the O'laho!a /ity proton therapy center, -ro/ure "or'ed "ith the
@elgiu!.based (@A, "hich pro$ided the center "ith its co!pact cyclotron, a !odel one 3uarter
the "eight o con$entional cyclotrons#
Sin&le2,ault )enter
Still *i$er Syste!s, head3uartered in 7ittleton, 9ass#, is also de$eloping a less costly proton
therapy syste!# @y early ne4t year, the co!pany plans to co!plete its irst pro1ect: a single.$ault
proton therapy center also e3uipped "ith co!pact technology# Ailiated "ith the Al$in +#
Site!an /ancer /enter at @arnes.+e"ish ,ospital and the 5ashington 0ni$ersity in St# 7ouis
School o 9edicine, the Iling /enter or -roton Therapy is scheduled to open in 2010,
according to its director, +erey D# @radley, 9D, an associate proessor o radiation oncology at
5ashington 0ni$ersity#
CThe hospital and uni$ersity "ere al"ays interested in proton therapy, as it could potentially
pro$ide ne" "ays to treat cancer, but the price tags or the acilities "ere too high,D says
@radley# C@ut Still *i$er de$eloped the concept o a co!pact cyclotron that supplies the proton
bea! "ithin a single roo!# That lo"ered the cost ro! about 2100 !illion to about 220 !illion
and greatly reduced acility si)e, "hich !ade proton therapy $iable or us#D
)losin& t#e Treatment 3ap
-rior to the O'laho!a centerBs opening, an esti!ated 2F0,000 0#S# patients stood to beneit ro!
proton therapy, but only =,000 treat!ent slots "ere a$ailable at the i$e e4isting centers# The
O'laho!a center alone "onBt signiicantly close that gap but represents a irst step to"ard
e4panding proton therapyBs reach and reducing its cost# -ro/ure is busy de$eloping a national
partnership net"or' o hospital. and co!!unity.based centers#
C5eBre loo'ing to open a second center in the /hicago area "ithin a year, and "eBre "or'ing on
t"o !ore pro1ects that should be co!pleted in 2011,D says /a!eron# C@eyond that, "eBll be
opening !ore centers in 2012, and this increasing acti$ity "ill boost the nu!ber o radiation
treat!ent slots#D
Still *i$er is "or'ing on se$en !ore pro1ects that are in $arious stages o de$elop!ent# The
co!pany is currently in$ol$ed in a pro1ect in Seattle "ith the S"edish /ancer (nstitute to
de$elop a 222 !illion proton therapy acility, the irst in the -aciic 8orth"est# C5eBre also
"or'ing "ith @ro"ard ,ealth in Fort 7auderdale to open a acility by 2012,D says 7ionel A#
@ouchet, -hD, Still *i$er Syste!Bs director o custo!er ser$ice and support# C5e ha$e other
pro1ects in 8e" @runs"ic', 8#+#; @oston; O'laho!a 0ni$ersity; Orlando, Fla#; and 7ong @each,
/ali#D
)osts: 1a4in& a )ase
-ro/ureBs =0,000.s3uare.oot /hicago.area acility, pro1ected to open in February 2010,
represents a partnership that includes *adiation Oncology /onsultants 7td <*O/7> and /entral
Du-age ,ospital, a J=1.bed acility in 5inield, (ll#
5hile -ro/ure again handled all o the logistics, cost consideration pro$ed crucial in this case,
says *O/7 -resident 5illia! F# ,artsell, 9D# C(nitial 3uotes or a t"o.roo! acility "ere in the
240.!illion range, and !ost o *O/7Bs potential hospital partners didnBt thin' it "as a good
in$est!ent# So, "e needed to state a con$incing case about proton $alue# That "asnBt too hard#
-roton treat!ent physics is !uch better than photon 4.ray physics#D
-roton therapy oers !ore precise control o$er the radiation energy deli$ered# The radiation
bea! deposits !ost o its energy directly into a tu!or# This allo"s physicians to ad!inister
higher, !ore eecti$e doses "hile reducing da!age to healthy surrounding tissue# (n contrast,
photons pass through a tu!or and e$en through the patient# The better radiation control helps
proton therapy patients e4perience e"er short. and long.ter! side eects, less ris' o secondary
tu!ors, and an i!pro$ed 3uality o lie# /linicians use proton therapy to treat cancers o the
brain, head and nec', spine, eye, esophagus, prostate, and breast# Also, because it !ini!i)es
long.lasting tissue da!age, proton therapy is particularly useul in treating pediatric patients#
/entral Du-age ,ospital "as ulti!ately con$inced to !o$e or"ard "ith the technology#
COb$iously, itBs not so!ething you 1ust buy o o the shel,D says ,artsell# C5e did a couple o
yearsB leg"or' and decided to partner "ith -ro/ure# Other co!panies "e spo'e "ith could
pro$ide technology but let the unding, design, and acility construction up to the custo!er#D
1a5or )#allen&e
Facility and e3uip!ent si)e is the biggest challenge in increasing proton therapy application# Still
*i$er and -ro/ure addressed the issue "ith inno$ati$e solutions# /ollaboration "ith the
9assachusetts (nstitute o Technology <9(T> led to de$elop!ent o the Still *i$er co!pact
cyclotron# (n 2004, the co!pany began "or'ing "ith scientists at 9(TBs -las!a Science K
Fusion /enter to de$elop a ne" high.ield !agnet# CThey "ere using state.o.the.art, super.
conducti$e !aterial to generate $ery high !agnetic ields,D e4plains @ouchet# CThese ields
enabled us to de$elop a ne" cyclotron "ith a !uch higher !agnetic ield# This allo"ed us to
greatly reduce the si)e o the proton source# /yclotrons at typical proton centers can "eigh as
!uch as 2F0 tons# Our cyclotron "eighs only 20 tons# 5e directly incorporate the cyclotron
"ithin the treat!ent roo!s, so in that sense, it is si!ilar to linear accelerators, "here e$erything
is installed in a single roo!#D
-ro/ure reduces the acility ootprint by decreasing the nu!ber o rotating gantries to a single
unit and by inno$ating ad$anced incline bea! and robotic positioning technology that reduces
e3uip!ent si)e, "eight, and cost#
CThe robotics and the incline bea! are the t"o !ost signiicant inno$ations that "e ha$e
incorporated in the past three or our years,D says /a!eron# COur robotic patient positioner
enables physicians to !o$e the patient in any direction# Also, in addition to a hori)ontal bea!,
"e ha$e a bea! inclined to J0 degrees $ertical# The coupling o these t"o inno$ations enables us
to treat about LFH o patients "ithout all o the gantries#D
Typical -ro/ure centers "ill include the ollo"ing:
M a 2J0. to 2F0.!egaelectron $olt, i4ed.energy, isochronous cyclotron that pro$ides a
continuous proton bea!;
M our treat!ent roo!s <t"o dual inclined.bea! roo!s, one i4ed hori)ontal.bea! roo!, and one
gantry treat!ent roo!>; and
M a therapy control syste! that pro$ides the interace to control and !onitor e3uip!ent to deli$er
sae and eecti$e treat!ent#
Addressin& )osts
5hile ne" technology has notably reduced price, cost re!ains a signiicant challenge# E$en
though the e3uip!ent and acility are s!aller, a center is still e4pensi$e to build, "ith total costs
ranging ro! 220 !illion to 22F !illion# To 1ustiy the inancial output and !eet e4penses, these
ne" acilities need suicient unding and patient throughput# Typically, acilities recei$e unding
ro! public and?or pri$ate sectors, according to -ro/ure# For instance, the -ro/ure -roton
Therapy /enter in O'laho!a /ity recei$ed an initial 270 !illion unding ro! energy e4ecuti$e
and philanthropist Aubrey I# 9c/lendon, coounder, chair!an, and /EO o O'laho!a /ity.
based /hesapea'e Energy /orporation# Also, as part o its business !odel, -ro/ure arranges
inancing and urther reduces client costs by in$esting its o"n capital resources# 5ith this
arrange!ent, -ro/ure assu!es !a1ority o"nership "hile the client beco!es a !inority o"ner#
Additionally, acilities need to deter!ine "hether they "ill ha$e the patient $olu!e to generate
acceptable return on in$est!ent# @oth the O'laho!a /ity and /hicago.area -ro/ure centers
e4pect an annual 1,F00.patient capacity#
That ties into patient de!and# (n O'laho!a, cancer is the second leading cause o death# The
stateBs health depart!ent reports that nearly 1L,000 ne" cases are diagnosed each year# C9any
patients are no" doing their o"n ho!e"or' $ia resources such as the (nternet,D says Aoad#
CTheyB$e learned !ore about their cancer and, in turn, the best treat!ent options# -atients ha$e
played a great part in putting the proton therapy issue on the table, "hich has helped the !edical
co!!unity push itsel outside o the bo4#D
0ntil recently, de!and or proton therapy a!ong physicians has been s!all, says /a!eron#
C@ecause o the e3uip!ent si)e and cost considerations, !any physicians didnBt aggressi$ely
pursue proton therapy, as they elt it "asnBt so!ething that "ould be a$ailable to patients#
-atients ha$e been !ore aggressi$e# TheyB$e beco!e !ore sophisticated about treat!ent options
and began as'ing !ore 3uestions# 5eBre helping physicians position the!sel$es to !eet the
increasing de!and,D he says#
Trainin& )#allen&e
5hile -ro/ure and Still *i$er ha$e de$eloped the e3uip!ent and business !odels to conront
de!and, training clinical sta to use proton therapy re!ains a challenge#
C8o" that the nu!ber o these ne" centers are increasing, proton therapy training is e!erging as
an i!portant issue,D says @radley# C(n our case, "eBre acti$ely training oursel$es# 5e ha$e
brought in e4perienced spea'ers, and "eBre sending sta to so!e o the larger proton therapy
centers, "here they can learn ho" to use the technology#D
-ro/ure includes a training co!ponent "ithin its business !odel and has established a training
center in @loo!ington# Aoad reports that beore the O'laho!a /ity center opened, neither he nor
!e!bers o his practice group had any e4perience "ith proton therapy# @ut theyB$e participated
in a training process that includes didactic, lab, and online learning ele!ents# CTraining needs to
be the ne4t !a1or step in radiation oncology as proton therapy is no" rapidly !o$ing or"ard,D
he says#
/a!eron says -ro/ureBs training is co!prehensi$e# C5e not only train people ho" to use the
technology, "e also train the! in all aspects o the business, ro! the ad!inistrati$e to the
physician le$els# Our broad.based training brings acilities 3uic'ly up to speed#D
-roton therapy is an e4tre!ely co!ple4 underta'ing, and co!!unity hospitals and physicians
groups can beneit ro! outside technological, inancial, and educational e4pertise to !a'e it
happen# As ,artsell indicates, it re3uires a three.part business collaboration# C(t re3uires a
partner that 'no"s ho" to build the acility, raise the unds, and supply the training; a hospital to
pro$ide a setting; and the physicians "illing to spend the ti!e and eort to bring proton therapy
into practice#D
Dan Harvey is a freelance writer based in Wilmington, Del., and a freqent contribtor
toRadiology Today.
Part II Peer Reviewed Article Review
-roessional peer re$ie"ed articles are address to a speciic audience, they are "ritten in
a or!al "riting, they support their inor!ation "ith studies, researches and data
pro$ided in the content# The !ethodology used needs to presented#%1&The "riters are
proessionals in the ield and their reerences are ro! other 1ournals# -eer re$ie"ed
articles ha$e to be appro$ed by other proessionals in the iled prior to being published#
The article has to contain the abstract, introduction, the !ethods, results, the discussion
related to the indings and the reerences#
( "ill re$ie" a research article entitled /linical Outco!es and To4icity o -roton @ea!
Therapy or Ad$anced /holangiocarcino!a, "ritten by 9a'ita /#, 8a'a!ura T#, Ta'ada
A#, et al#, all these proessionals are ro! se$eral !edical institutions, graduate schools o
!edicine and a proton center# The article "as published in *adiation Oncology +ournal# (
"ill "rite a brie re$ie" and "ill obser$e i the article "as "ritten to !eet the
proessional peer re$ie"ed article criteria#
(n the abo$e !entioned article there "as a research conducted to deter!ine the eicacy
and to4icity o the proton radiation bea! in treating patients "ith ad$anced
cholangiocarcino!a#%2& (n the bac'ground the authors discussed the pathology;
cholangiocarcino!a is a tu!or that arises ro! the epitheliu! o the bile ducts and it is
rarely operable# The radiation treat!ent "ith 6.rays is doubtable due to the radio
sensiti$ity o the structures surrounding the area# (n 2009 a proton radiation treat!ent
study started, there "ere considered patients "ith unresectable and inoperable
cholangiocarcino!a, or recurrent tu!ors# The 2L patients "ere treated bet"een 2009 and
2011 "ith proton energy le$els o 1F0 and 210 9eN# A respiratory gating syste! "as
used to synchroni)e the treat!ent in the e4piratory phase# The !edian radiation dose
deli$ered "as =L#2 Ay# Ater the treat!ent, there "as a ollo".up and to4icity e$aluation
or e$ery J !onths up to 2 years# This "as done using i!aging !ethods li'e /T, 9*(,
-ET?/T scans and lab analysis# The results o the study de!onstrated that out o the total
o 2L patients, = o the! sho"ed signs o duodenal to4icity, and this could ha$e sho"n as
a side eect ro! the che!otherapy, too# For the rest o the patients, proton radiation
treat!ent "as easible, "ith tolerable to4icity le$els# /onclusion o the study "as that
urther in$estigation is needed to deter!ine i the to4icity le$els "ere caused by
che!otherapy or by the proton radiation bea!#
( ound this article $ery interesting, "ith all the re3uired research criteria !et# The study
is a door opener or urther in$estigation and raises a"areness to"ards the treat!ent
!odalities or cholangiocarcino!a# The results "ere supported by $alid data and the
conclusion "as su!!ari)ed properly# (nor!ation is accurate, recent and the reerences
are pro$ided# (t is a con$enient reading, "ith a good choice o "ords# This article is a
great educational tool or the radiation oncology proessionals, !edical dosi!etrists and
students in the ield#
References:
1# 7enards 8#, 5eege 9# Radiation Therapy and Medical Dosimetry Reading#
%-o"erpoint&# 7a /rosse, 5(: 05.7 9edical Dosi!etry -rogra!; 2014#
2# 9a'ita /#, 8a'a!ura T#, Ta'ada A#, et al# /linical outco!es and to4icity o proton bea!
therapy or ad$anced cholangiocarcino!a# Radiation !ncology# 2014; 9<2=>#
http:??"""#ro.1ournal#co!?content?9?1?2= # Accessed February 19, 2014#
Researc#
)linical outcomes and to6icit$ of proton beam t#erap$ for advanced c#olan&iocarcinoma
)#i$o4o 1a4ita1
O
, Tatsu$a .a4amura2, A4inori Ta4ada1, 7ana4o Ta4a$ama1,1oto#isa
Su8u4i1, 9o5iro Is#i4awa1, 9usu4e A8ami1, Ta4a#iro 7ato1, Iwao Tsu4i$ama1, 9asu#iro
7i4uc#i1, 1asato +are$ama1, 1asao 1ura4ami2, .obu4a8u (uwaJ, 1asa#aru
+ata4 and Tomio Inoue4
O/orresponding author: /hiyo'o 9a'ita chio'o.!a'itaPli$e#1p
Author Ailiations
1
Depart!ent o *adiation Oncology, Southern Toho'u -roton Therapy /enter, 7.172,
Qatsuya!ada, 9=J.L0F2 Ioriya!a, Fu'ushi!a, +apan
2
Depart!ent o *adiology, Araduate School o 9edicine, Do''yo 9edical 0ni$ersity, LL0
Iita'obayashi, 9ibu.!achi, J21.029J Shi!otsuga, Tochigi, +apan
J
,yogo ion bea! 9edical /enter, 1.2.1 Ioto, Shingu, =79.F1=F Tatsuno, ,yogo, +apan
4
Depart!ent o *adiology, Araduate School o 9edicine, Qo'oha!a /ity 0ni$ersity, J.9
Fu'uura, 2J=.0004 Iana)a"a.'u, Qo'oha!a, +apan
For all author e!ails, please log on#
Radiation !ncology 2014, ":2= doi:10#11L=?174L.7176.9.2=
The electronic $ersion o this article is the co!plete one and can be ound online
at:http:??"""#ro.1ournal#co!?content?9?1?2=
*ecei$ed: 1L 9arch 201J
Accepted: 9 +anuary 2014
-ublished: 14 +anuary 2014
R 2014 9a'ita et al#; licensee @io9ed /entral 7td#
This is an open access article distributed under the ter!s o the /reati$e /o!!ons Attribution
7icense <http:??creati$eco!!ons#org?licenses?by?2#0>, "hich per!its unrestricted use,
distribution, and reproduction in any !ediu!, pro$ided the original "or' is properly cited#
Abstract
*ac4&round
5e e4a!ined the eicacy and to4icity o proton bea! therapy <-@T> or treating ad$anced
cholangiocarcino!a#
1et#ods
The clinical data and outco!es o 2L cholangiocarcino!a patients treated "ith -@T bet"een
+anuary 2009 and August 2011 "ere retrospecti$ely e4a!ined# The IaplanS9eier !ethod "as
used to esti!ate o$erall sur$i$al <OS>, progression.ree sur$i$al <-FS>, and local control <7/>
rates, and the log.ran' test to analy)e the eects o dierent clinical and treat!ent $ariables on
sur$i$al# Acute and late to4icities "ere assessed using the 8ational /ancer (nstitute /o!!on
Ter!inology /riteria or Ad$erse E$ents $ersion 4#0#
Results
The !edian age o the 17 !ale and 11 e!ale patients "as 71 years <range, 41 to L4 years;
intrahepatic?peripheral cholangiocarcino!a, n T =; hilar cholangiocarcino!a?Ilats'in tu!or, n T
=; distal e4trahepatic cholangiocarcino!a, n T J; gallbladder cancer, n T J; local or ly!ph node
recurrence, n T 10; si)e, 20S17F !!; !edian F2 !!># The !edian radiation dose "as =L#2 Ay
<relati$e biological eecti$eness %*@E&> <range, F0#= to L0 Ay <*@E>>, "ith deli$ery o ractions
o 2#0 to J#2 Ay <*@E> daily# The !edian ollo".up duration "as 12 !onths <range, J to 29
!onths># Fiteen patients under"ent che!otherapy and L patients, palliati$e biliary stent
place!ent prior to -@T# OS, -FS, and 7/ rates at 1 year "ere 49#0H, 29#FH, and =7#7H,
respecti$ely# 7/ "as achie$ed in = patients, and "as better in patients ad!inistered a
biologically e3ui$alent dose o 10 <@ED10> U 70 Ay co!pared to those ad!inistered V 70 Ay
<LJ#1H $s# 22#2H, respecti$ely, at 1 year># The $ariables o tu!or si)e and peror!ance status
"ere associated "ith sur$i$al# 7ate gastrointestinal to4icities grade 2 or greater "ere obser$ed in
7 patients V12 !onths ater -@T# /holangitis "as obser$ed in 11 patients and J patients re3uired
stent replace!ent#
)onclusions
*elati$ely high 7/ rates ater -@T or ad$anced cholangiocarcino!a can be achie$ed by
deli$ery o a @ED10 U 70 Ay# Aastrointestinal to4icities, especially those o the duodenu!, are
dose.li!iting to4icities associated "ith -@T, and early !etastatic progression re!ains a
treat!ent obstacle#
7e$words:
/holangiocarcino!a; -roton bea! therapy; /he!oradiotherapy; /holangitis; Aastrointestinal
to4icity
*ac4&round
/holangiocarcino!a is a !alignant tu!or arising ro! the epitheliu! o the bile ducts# (t is
esti!ated that 2J,000 cases o cholangiocarcino!a are diagnosed in +apan e$ery year, an
incidence higher than that in "estern countries %1&# Although surgery is the only potentially
curati$e treat!ent or cholangiocarcino!a, only 10H to J0H patients are candidates or surgery
at presentation %2&# The !a1ority o patients present "ith either locally ad$anced or distant
!etastatic disease# E$en or patients in "ho! curati$e resection is peror!ed, the prognosis
re!ains poor; local ailure rates are high, and death ro! biliary obstruction, sepsis, and li$er
ailure is co!!on# For patients "ith unresectable cholangiocarcino!a, sur$i$al is poor, ranging
ro! J to 9 !onths in those recei$ing !edical !anage!ent alone due to tu!or
aggressi$eness %2.4&#
Treat!ent o cholangiocarcino!a by con$entional o radiotherapy is contro$ersial or se$eral
reasons %F&# These include re3uent local and regional recurrence despite pro$ision o deiniti$e
che!oradiotherapy; radiation intolerance, "hich li!its the dose that !ay be deli$ered to the
entire li$er, pro4i!al biliary tract, and digesti$e tract %=&; and inability to deli$er high dose 6.
rays to the tu!or# ,o"e$er, using charged.particle therapy, superior dose distribution can be
achie$ed due to the e4istence o the @ragg pea', "hich enables deli$ery o higher doses o
radiation to tu!or tissue "ithout increasing e4posure to the surrounding nor!al tissue#
Schoenthaler et al# reported pro$iding charged.particle therapy using heliu! and?or neon to treat
22 patients "ith e4trahepatic bile duct carcino!a %7&# (!pro$ed !edian sur$i$al has been
obser$ed in patients "ith !icroscopic residual disease "ith the addition o ad1u$ant irradiation
ater charged.particle therapy, also in co!parison to patients treated "ith con$entional
radiotherapy# Since +anuary 2009, ad$anced cholangiocarcino!a has been treated at our
institution "ith proton bea! therapy <-@T>, a or! o charge.particle therapy# Despite the
potential o this or! o treat!ent, to our 'no"ledge no other study has e4a!ined its use in
treating this patient population# To ill this research gap, this study retrospecti$ely e$aluated the
eicacy and to4icity o -@T or the treat!ent o unresectable and inoperable
cholangiocarcino!a#
1et#ods
Patients
@et"een +anuary 2009 and August 2011, 2L patients "ith ad$anced cholangiocarcino!a <1L
patients "ith unresectable cholangiocarcino!a and 10 "ith recurrent tu!or ater surgery> "ere
treated "ith -@T at our institution# The initial "or'up or these patients had generally included
ta'ing a !edical history; peror!ing a physical e4a!ination; conducting laboratory testing or a
co!prehensi$e !etabolic panel and !easure!ent o co!plete blood cell count,
carcinoe!bryonic le$el, and carbohydrate antigen 19S9 le$el; and conducting chest 6.ray,
electrocardiogra!, co!puted to!ography </T> "ith positron e!ission to!ography <-ET> using
2.<luorine.1L>.luoro.2.deo4y.D.glucose <FDA.-ET?/T>, enhanced abdo!inal /T# 9agnetic
resonance i!aging <9*(> "as peror!ed on so!e patients to get additional inor!ation#
,istological diagnosis o cholangiocarcino!a had been deter!ined in all ne"ly diagnosed
patients prior to initiation o -@T# -athological diagnosis o recurrent cases had been !ade prior
to surgery#
@iopsy procedures had typically in$ol$ed endoscopic retrograde cholangiopancreatography "ith
or "ithout endoscopic ultrasonography# *esectability had been deter!ined by indi$idual hepatic
surgeons# 8o e$idence o distant !etastases had been ound at the ti!e o -@T initiation in any
patient# Abdo!inal surgical staging had been peror!ed in 1 patient, biliary stenting to relie$e
sy!pto!s in L patients "ith biliary obstruction, ultrasound.guided percutaneous transhepatic
biliary drainage in J patients, and endoscopic retrograde biliary drainage in F patients# -atients
"ith carcino!a o the a!pulla o Nater "ere e4cluded ro! this study#
Treatment
All patients had undergone si!ulation using a 1=.slice large.bore helical /T scanner <A3uilion
7@; Toshiba, To'yo, +apan> and a respiratory gating syste! <An)ai 9edical, To'yo, +apan>#
0sing this syste!, /T i!ages had been obtained in the e4halation phase, and a con$entional
scan "ith a 2.!! slice thic'ness had been obtained# A custo!.induced $acuu!.loc' bag
<Esor!; Engineering Syste! /o#, 9atsu!oto, +apan> had been used or patient i!!obili)ation#
Diagnostic /T or 9*( i!ages had been used "ith planning /T i!ages or target delineation#
For -@T planning, a J.di!ensional treat!ent planning syste! <6io.9; /9S +apan, To'yo,
+apan; 9itsubishi Electric /orporation, Iobe, +apan> had been used# Aross tu!or $olu!e had
been identiied ro! re$ie" o these i!ages by the li$er surgeon, gastroenterologist, and
diagnostic radiologists#
The clinical target $olu!e had included a F. to 10.!! radial e4pansion o the gross tu!or
$olu!e to target possible !icroscopic disease e4tension# *egional ly!ph nodes had not been
intentionally co$ered unless pathologically enlarged# The planning target $olu!e had been
e4panded by F !! in all directions to create an additional F. to 7.!! !argin in the craniocaudal
direction to co!pensate or respiratory !o$e!ents# The photon plan "as co!pared "ith the
doseS$olu!e histogra!, although con$entional planning target $olu!e is not typically used in
proton planning# The total dose at the isocenter had been prescribed to co$er 90H o the planning
target $olu!e# Doses had been calculated on the basis o the pencil bea! algorith!# -roton
energy le$els o 1F0 and 210 9eN or 1 to 4 portals had been planned#
The -@T syste! <-roton Therapy Syste!; 9itsubishi> uses a synchrotron that could accelerate
protons up to 2JF 9eN# A respiratory gating syste! <An)ai 9edical, To'yo, +apan> had been
used to synchroni)e treat!ent in the e4piratory phase# The relati$e biological eecti$eness o the
proton bea! had been deter!ined to be 1#1# The !edian radiation dose had been =L#2 Ay
<relati$e biological eecti$eness %*@E&> <range, F0#= to L0 Ay <*@E>>, "ith deli$ery o ractions
o 2#0 to J#2 Ay <*@E> daily, depending on tu!or location# (n cases in "hich the tu!or had been
ad1acent to the digesti$e tract, a dose o 2#0 to 2#2 Ay <*@E> per raction had been deli$ered# (n
cases in "hich the tu!or had been greater than 2 c! ro! the gastrointestinal tract and porta
hepatis, a dose o J#2 Ay <*@E> per raction had been deli$ered#
(ollow2up and to6icit$ evaluation
Abdo!inal i!aging studies </T, 9*(, or FDA.-ET?/T> and lab analyses <including
!easure!ent o tu!or !ar'er le$els> had been peror!ed e$ery J !onths ater -@T or the irst
2 years# (n cases in "hich obstructi$e 1aundice and hyperbilirubine!ia had persisted ater
co!pletion o -@T, additional radiological analyses had been peror!ed to e$aluate local ailure#
(n the subse3uent analysis o outco!es, local control <7/> "as deined as no sign o regro"th or
ne" tu!or de$elop!ent in the target area# Acute and late to4icities "ere assessed using the
8ational /ancer (nstitute /o!!on Ter!inology /riteria or Ad$erse E$ents $ersion 4#0# To
e$aluate post.treat!ent late to4icity in the duodenu!, doseS$olu!e histogra!s "ere de$eloped
or cases deli$ered a @ED o J#
Statistical anal$sis
Obser$ation o endpoints began on the sa!e date on "hich proton therapy "as initiated# The
IaplanS9eier !ethod "as used to esti!ate o$erall sur$i$al <OS>, progression.ree sur$i$al
<-FS>, and 7/ and the log.ran' test to analy)e the eects o dierent clinical and treat!ent
$ariables on sur$i$al# All statistical analyses "ere peror!ed using S-SS sot"are $ersion 1L#0
<S-SS, /hicago, (7, 0SA>#
:t#ical approval
This study "as appro$ed by an institutional co!!ittee o Southern Toho'u -roton Therapy
/enter# The research "as in co!pliance "ith the ,elsin'i Declaration#
Results and discussion
Patient, tumor, and treatment c#aracteristics
Table 1 lists the patient and tu!or characteristics# The !edian age o the 17 !ale and 11 e!ale
patients had been 71 years <range, 41 to L4 years># O the 2L patients, = had been ne"ly
diagnosed "ith intrahepatic cholangiocarcino!a, = "ith hilar cholangiocarcino!a <Ilats'in
tu!or>, J "ith distal e4trahepatic cholangiocarcino!a, and J "ith gallbladder cancer# Se$en
patients had e4perienced local recurrence and J ly!ph node recurrence# -@T had been
ad!inistered to recurrent cases 12 to 40 !onths ater surgery# Tu!ors treated "ith -@T had
ranged in si)e ro! 20 to 17F !! <!edian, F2 !!> in the greatest di!ension#
Table -. Patient and tumor c#aracteristics
Table 2 lists the treat!ent characteristics o the patients e4a!ined in this study# @ecause $arious
ractionation regi!ens had been used or treat!ent, a biologically e3ui$alent dose <@ED> "as
calculated or co!parison using the linearS3uadratic !odel# Assu!ing a @ED o 10 <i#e#,
@ED10; W?X T 10> or tu!or control, the esti!ated !edian @ED10 had been 7F#L Ay <range, =1#7
to 10F#= Ay># Assu!ing a @ED o J <@EDJ; W?X T J> or cases in "hich late to4icity had been
obser$ed, the esti!ated !edian @EDJ had been 10=#L Ay <range, 9F#J to 1=F#J Ay>#
/he!otherapy consisting o ge!citabine and?or tegaur, gi!eracil, and either oteracil <S.1> or
cisplatin beore or ater -@T had been ad!inistered to 1F patients, and S.1 had been
ad!inistered concurrently "ith -@T treat!ent to J patients#
Table . Patient treatment c#aracteristics
)linical outcomes
A!ong all patients, the !edian ollo".up duration had been 12 !onths <range, J to 29 !onths>
and OS and -FS at 1 year had been 49#0H <9FH conidence inter$al %/(& F9#1H to JL#9H> and
29#FH <9FH /( J9#JH to 19#7H>, respecti$ely <Figure 1># 0ni$ariate analysis identiied a
signiicant relationship bet"een sur$i$al and the $ariables o tu!or si)e and peror!ance
status,but not bet"een sur$i$al and the $ariables o age, gender, tu!or !ar'ers, and
che!otherapy <Table J># O the 19 patients <=7#9H> "ho had e4perienced recurrence during the
obser$ation period, = patients <21#4H> had de$eloped local recurrence, F patients <17#9H> ne"
intrahepatic tu!ors, F patients <17#9H> peritonitis carcino!atosa, 2 patients <7#1H> distant
!etastases, and 1 patient <J#=H> ly!ph node !etastases# O the 1= patients <F7#1H> "ho had
died during the obser$ation period, the death o 14 patients <had been attributed to
cholangiocarcino!a; the death o 1 patient <J#=H> to cholangitis.related disse!inated
intra$ascular coagulation ater replace!ent o the biliary stent, "hich had caused peroration o
the bile duct; and the death o 1 patient <J#=H> to lung cancer# The 7/ rate at 1 year had been
=7#7H <9FH /( 79#1 to F=#J># 0ni$ariate analysis indicated better 7/ in patients to "ho! a
@ED10 greater than 70 Ay -@T had been ad!inistered co!pared "ith those to "ho! a @ED10
less than 70 Ay had been ad!inistered <LJ#1H $s# 22#2H, respecti$ely, at 1 year; p T 0#002>
<Figure 2>#
(i&ure -. ;verall survival and pro&ression2free survival. 9edian o$erall
sur$i$al "as 12#0 !onths and !edian progression.ree sur$i$al L#0 !onths#
Table <. =nivariate anal$sis of factors potentiall$ affectin& overall survival
(i&ure . >ocal control stratified accordin& administration of *:'-! ?7! 3$
or @ 7! 3$.
To6icit$
Table 4 lists the acute and late to4icities that had been e4perienced by the patients# Eight patients
had de$eloped acute treat!ent.related to4icities o grade 2 or greater in the or!s o
thro!bocytopenia, erythe!a, anore4ia, abdo!inal pain, diarrhea, and cholangitis# Si4 patients
had de$eloped late to4icities o cholangitis o grade 2 or J# One patient had been diagnosed "ith
grade 2 co!!on bile duct stenosis# All patients "ith acute and late treat!ent.related cholangitis
had been treated "ith intra$enous antibiotics, and J had re3uired stent replace!ent# 7ate
gastrointestinal to4icities o grade 2 or greater had been e4perienced by 7 patients "ithin 12
!onths ater -@T in the or!s o duodenal ulcer in 2 patients, duodenal he!orrhage in 2
patients, duodenal stenosis in 2 patients, and gastric ulcer in 1 patient# O the 1F patients <FJ#=H>
"ho had undergone irradiation o the duodenu!, the !ean irradiated $olu!e e4ceeding a @EDJ
o L0 Ay to the duodenu! had been 11#0 Y 4#J !l# O the = patients "ho had e4perienced
duodenal.related to4icities, the !ean irradiated $olu!e e4ceeding a @EDJ o L0 Ay to the
duodenu! had been 21#0 Y F#1 !l#
Table 0. Acute and late to6icities e6perienced durin& observation period
(n patients "ith unresectable cholangiocarcino!a, palliati$e irradiation ollo"ing biliary
deco!pression has been sho"n to prolong sur$i$al %J&# Although patients "ith postoperati$e
local or regional recurrence are treated "ith radiotherapy, no deiniti$e treat!ent has yet been
established# @ecause no global consensus e4ists or treat!ent o ad$anced cholangiocarcino!a,
$arious palliati$e therapies ha$e been ad!inistered to atte!pt to i!pro$e sur$i$al and 3uality o
lie, including e4ternal bea! radiotherapy <E@*T>, brachytherapy, syste!ic che!otherapy,
radiore3uency ablation, and transarterial che!oe!boli)ation %L,9&# @ecause o their ability to
deli$er !ar'edly higher doses o radiation directly to tu!or tissue, intensity.!odulated
radiotherapy and stereotactic body radiotherapy ha$e also been utili)ed %10,11&#
A!ong the treat!ent options that ha$e been e4a!ined, one study in$estigated therapy using
charged particles, such as neon and heliu! ions, in the treat!ent o e4trahepatic bile duct
carcino!a "ith !icroscopically positi$e !argins ater surgery in 22 patients %7&# Deli$ering a
total dose ranging ro! 4L00 to =77L cAy <!edian, =000 cAy> "ith curati$e intent, a trend
to"ard i!pro$ed outco!e in patients treated "ith neon "as obser$ed, "ith the !edian sur$i$al
o these patients ound to be 2F !onths co!pared to 12#F !onths "ith heliu! and 11 !onths
"ith photon therapy#
(n an eort to !a4i!i)e outco!es in patients "ith ad$anced cholangiocarcino!a "ho are
treated radiotherapeutically, se$eral studies ha$e in$estigated the presu!ed correlation bet"een
tu!or dose and sur$i$al# Alden and 9ohiduddin reported an i!pro$e!ent in the 2.year sur$i$al
rate <4LH $s# 0H, p T 0#0J> and !edian sur$i$al duration <24 !onths $s# = !onths> "ith
treat!ent "ith E@*T and brachytherapy deli$ering total doses greater than FF Ay %12&# Nale' et
al# ound that ad!inistration o intralu!inal brachytherapy signiicantly prolonged sur$i$al and
sy!pto!.ree duration in patients "ith unresectable cholangiocarcino!a "ho had undergone
stent replace!ent %1J&# (!pro$ed 7/ and OS ha$e also been obser$ed "ith higher radiation
doses, suggesting that dose escalation !ay be a pro!ising therapeutic approach# On the other
hand, /rane et al# ound that the addition o brachytherapy pro$ided no beneit %14&# Although
"e did obser$e a better 7/ in patients ad!inistered a @ED10 o greater than 70 Ay -@T
co!pared to those recei$ing a @ED10 o less than 70 Ay <L9H $s# J=H, respecti$ely, at 1 year>,
no sur$i$al beneit "as ound "ith ad!inistration o a higher proton dose in the current study#
The role o che!otherapy in treating cholangiocarcino!a is unclear# Iopleson et al# asserted the
easibility and potential beneit o che!otherapy in addition to radiation %1F&# Deodato et al# also
reported that concurrent che!otherapy "ith F.luorouracil appeared to i!pro$e outco!e based
on obser$ation o a !edian sur$i$al o 22 !onths and a 2.year sur$i$al rate o 41H %1=&# (n
contrast, /rane et al# ound no sur$i$al beneit o concurrent che!oradiation %14&# (n accordance
"ith the indings o /rane et al# %14&, co!bined che!otherapy and -@T "as ound to pro$ide no
sur$i$al beneits to the patients in the current study, in "ho! early !etastatic progression o the
li$er, regional ly!ph nodes, and distant lesions re!ained !a1or treat!ent obstacles# A!ong all
patients in this study, 19 <=7#9H> e4perienced tu!or recurrence, "ith 1J <4=#4H> o these 19
patients de$eloping recurrent tu!ors outside o the proton.irradiated ield, a!ong the! the 7
patients "ho had been undergone che!otherapy# Further study is needed to deine the roles o
che!otherapy and -@T in cholangiocarcino!a#
-otential acute to4icities o co!bined E@*T and che!otherapy include nausea, $o!iting,
anore4ia, dehydration, s'in reaction, gastritis, duodenitis, atigue, and li$er dysunction %1F.17&#
(n a study o a series o L1 patients "ith e4trahepatic cholangiocarcino!a "ho under"ent
co!bined che!otherapy and radiotherapy, @en.Da$id et al# obser$ed de$elop!ent o late
co!plications <ulcer or!ation, gastritis, and?or $eno.occlusi$e disease o the li$er> in F patients
"ith hilar carcino!a at a !edian o = !onths ater treat!ent %17&# *egarding the eect o
$olu!e on the de$elop!ent o gastrointestinal to4icity, E!ani et al# esti!ated a dose o 1?J or
s!all bo"el irradiation <i#e#, F0 Ay> based on the probability o a FH co!plication "ithin the F
years ollo"ing irradiation <i#e#, a tolerance dose %TD& o F?F># E!ani et al#Bs esti!ation re!ains
a co!!only applied dose li!it "hen s!all portions o the s!all bo"el are treated "ith a
con$entional raction# Despite this esti!ation, the probability o a F0H co!plication "ithin the F
years ollo"ing irradiation <TDF0?F> or partial s!all bo"el irradiation <i#e#, deli$ery o =0 Ay>
re!ains une4plored%1L&# The !ini!u! tolerable radiation dose to the duodenu! that results in
TD F?F is F0 Ay "ith ractions o 1#L Ay?day, a dose e3ui$alent to a @EDJ o L0 Ay#
Although duodenal co!plications "ere obser$ed in = patients in the current study, 1F o the 2L
patients <FJ#=H> had undergone duodenal irradiation at a !ean $olu!e o @EDJ o UL0 Ay o
11#0 Y 4#J !l# (n the = patients in "ho! duodenal to4icities occurred, the irradiated $olu!e to
the duodenu! <@EDJ o UL0 Ay> "as 21#0 Y F#1 !l# To !ini!i)e to4icity in patients "ith
cholangiocarcino!a ad1acent to the gastrointestinal tract, especially the duodenu!, the irradiated
$olu!e o duodenal irradiation should be decreased in -@T#
Due to li!itations o the present study such as s!all nu!ber o patients, heterogeneous doses,
and retrospecti$e nature, opti!al -@T doses and che!otherapy regi!en are still unclear# @ut "e
indicate the potential beneit and to4icity proile o -@T or ad$anced cholangiocarcino!a#
Further in$estigations are "arranted#
)onclusion
(n conclusion, the study results indicate that -@T is an eecti$e, as e$idenced by the high 7/
rates o patients ad!inistered a @ED10 greater than 70 Ay, as "ell as easible, as e$idenced by
the tolerable to4icity le$els o all patients e4cept those = "ho e4perienced duodenal to4icity,
or! o treat!ent or cholangiocarcino!a# 8e$ertheless, early !etastatic progression re!ains a
!a1or obstacle since -@T !ay not be eecti$e in those cases# Further study is needed to deine
the roles o che!otherapy and -@T in cholangiocarcino!a treat!ent#
Abbreviations
@ED: @iologically e3ui$alent dose; 7/: 7ocal control; OS: O$erall sur$i$al; -@T: -roton bea!
therapy; -FS: -rogression.ree sur$i$al; *@E: *elati$e biological eecti$eness#
)ompetin& interest
The authors declare that they ha$e no co!peting interests#
Aut#orsA contributions
T8, AT, IT, 9S, Q(, and QA treated all o the patients "ith -@T# 8F participated in the design
o the study# TI chec'ed and calculated all the plans# 99, (T, 99 and 9, concei$ed the
study, participated in its design and coordination, and helped to drat the !anuscript# All authors
read and appro$ed the inal !anuscript#
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