O iginal Resea ch A icle
Con ac X- ay B achy he apy as a sole ea men in selec ed pa ien s wi h
ea ly ec al cance – Mul i-cen e s udy
Ngu Wah Than
a,b
, D. Ma k P i cha d
a
, Da id M. Hughes
c
, Kai Shing Yu
d
, Helen S. Minnaa
d
,
Amandeep Dhadda
e
, Jamie Mills
, Joakim Folkesson
g
, Calin Radu
h
, C.A. Duckwo h
a
,
Helen Wong
b
, Muneeb Ul Haq
a,b
, Raja am S ipadam
b
, Ma k D. Halling-B own
d
,
Alexand a J. S ewa
d,i
, A hu Sun Myin
a,b,*
a
Depa men o Molecula and Clinical Cance Medicine, Ins i u e o Sys ems, Molecula and In eg a i e Biology, The Uni e si y o Li e pool, L69 3GE, UK
b
The Cla e b idge Cance Cen e NHS Founda ion T us , 65 Pemb oke Place, Li e pool L7 8YA, UK
c
Depa men o Heal h Da a Science, Ins i u e o Popula ion Heal h, The Uni e si y o Li e pool, L7 3EA, UK
d
S . Luke’s Cance Cen e, Royal Su ey Hospi al, Guild o d, Su ey, UK
e
Cas le Hill Hospi al, Cas le Road, Co ingham HU16 5JQ, UK
No ingham Uni e si y Hospi als NHS T us , No ingham Ci y Hospi al, Hucknall Rd, No ingham NG5 1PB, UK
g
Depa men o Su ge y, Akademiska sjukhuse , Ins i u e o Su gical Sciences, Uppsala Uni e si y, 751 85 Uppsala, Sweden
h
Depa men o Immunology, Gene ics and Pa hology, Expe imen al and Clinical Oncology, Uppsala Uni e si y, 751 85 Uppsala, Sweden
i
Uni e si y o Su ey, Guild o d, Su ey, UK
ARTICLE INFO
Keywo ds:
Rec al cance
Con ac X- ay B achy he apy
Papillon
O gan p ese a ion
Sole ea men
ABSTRACT
Backg ound and pu pose: Radical su ge y is he s anda d o ca e o ea ly ec al cance . Howe e , al e na i e
o gan-p ese ing app oaches a e a ac i e, especially in ail o elde ly pa ien s as hese a oid su gical com-
plica ions. We ha e assessed he e icacy o sole Con ac X- ay B achy he apy (CXB) ea men in s age-1 ec al
cance pa ien s who we e unsui able o o declined su ge y.
Ma e ials and me hods: This e ospec i e mul i-cen e s udy (2009–2021) e alua ed 76 pa ien s wi h T1/2-N0-
M0 ec al adenoca cinomas who we e ea ed wi h CXB alone. Ou comes we e assessed o he en i e coho
and sub-g oups based on he T-s age and he c i e ia o ecei ing CXB alone; G oup A: pa ien s who we e i
enough o su ge y bu declined, G oup B: pa ien s who we e high- isk o su ge y and G oup C: pa ien s who had
ecei ed p io pel ic adia ion o a di e en cance .
Resul s: Wi h a median ollow-up o 26(IQR:12–49) mon hs, ini ial clinical Comple e Response (cCR) was 82
(70–93)% wi h a es o local eg ow h 18(8–29)%, 3-yea ac ua ial local con ol (LC) 84(75–95)%, dis an
elapse 3 %, and no nodal elapse. 5-yea disease- ee su i al (DFS) and o e all su i al (OS) we e 66(48–78)%
and 58(44–75)%. Lowe OS was obse ed in G oups B [HR:2.54(95 %CI:1.17, 5.59), p =0.02] and C [HR:2.75
(95 %CI:1.15, 6.58), p =0.03]. P e ious pel ic adia ion p edic ed lowe cCR and OS. The main oxici y was G1-
2 ec al bleeding (26 %) and symp oms o impai ed anal sphinc e unc ion we e no epo ed in any pa ien s.
Conclusion: CXB ea men alone achie ed a high cCR a e wi h sa is ac o y LC and DFS. In e io oncological
ou comes we e obse ed in pa ien s who had ecei ed p io pel ic adio he apy. CXB alone, wi h i s a ou able
oxici y p o ile and a oidance o gene al anaes hesia and su ge y isks, he e o e, can be conside ed o pa ien s
who a e unsui able o o e use su ge y.
* Co esponding au ho a : The Cla e b idge Cance Cen e NHS Founda ion T us , 65 Pemb oke Place, Li e pool L7 8YA, UK.
E-mail add esses: [email p o ec ed] (N. Wah Than), [email p o ec ed] (D. Ma k P i cha d), [email p o ec ed] (D.M. Hughes), k.
[email p o ec ed] (K. Shing Yu), [email p o ec ed] (H.S. Minnaa ), [email p o ec ed] (A. Dhadda), [email p o ec ed] (J. Mills), joakim. olkesson@
uu.se (J. Folkesson), [email p o ec ed] (C. Radu), [email p o ec ed] (C.A. Duckwo h), [email p o ec ed] (H. Wong), Muneeb.Haq@
li e pool.ac.uk (M. Ul Haq), [email p o ec ed] (R. S ipadam), [email p o ec ed] (M.D. Halling-B own), [email p o ec ed]
(A.J. S ewa ), [email p o ec ed] (A. Sun Myin ).
Con en s lis s a ailable a ScienceDi ec
Clinical and T ansla ional Radia ion Oncology
jou nal homepage: www.sciencedi ec .com/jou nal/clinical-and- ansla ional- adia ion-oncology
h ps://doi.o g/10.1016/j.c o.2024.100851
Recei ed 12 July 2024; Recei ed in e ised o m 29 Augus 2024; Accep ed 1 Sep embe 2024
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
A ailable online 6 Sep embe 2024
2405-6308/© 2024 The Au ho (s). Published by Else ie B.V. on behal o Eu opean Socie y o Radio he apy and Oncology. This is an open access a icle unde
he CC BY license ( h p://c ea i ecommons.o g/licenses/by/4.0/ ).
In oduc ion
The s anda d managemen o ea ly ec al cance (T1/T2-N0-M0)
in ol es o al meso ec al excision (TME) [1,2]. This modali y o e s an
imp essi e cu e a e (90–94 %) and 5-yea su i al a es exceeding 90 %
[3]. Howe e , i is associa ed wi h inc eased isks o pos ope a i e
complica ions and impac s upon long- e m unc ional ou comes [4,5].
Especially in pa ien s wi h ad ancing age and hose wi h mul iple
como bidi ies [6].
O e he las decade, inc eased de ec ion o ea ly-s age ec al cance s
h ough na ional bowel cance sc eening p og ammes [7,8], a highe
incidence o bowel cance in he elde ly [9], and he inc eased p e a-
lence o medical como bidi ies associa ed wi h ad ancing age [10],
suppo he use o o gan-p ese ing ea men s. These include ansanal
excision (TAE) o endoscopic mucosal esec ion (EMR) wi h o wi hou
adju an adio he apy, and non-su gical ea men modali ies including
ex e nal beam (chemo) adia ion (EBRT/EBCRT), o exclusi e endoca-
i a y adio he apy [11–16]. Adop ing hese mo e conse a i e s a e-
gies aims o minimise pos -su gical complica ions, dec ease mo ali y
a es, and enhance pa ien s’ o e all quali y o li e [17,18].
Since i s in oduc ion as a ec al cance ea men , Con ac X- ay
B achy he apy (CXB) has been used as a s andalone he apy o e y
ea ly-s age umou s and can be supplemen ed by he inco po a ion o
EBRT o in e s i ial b achy he apy using I idium (
192
I ) [19,20]. Sole
CXB ea men emains an a ac i e op ion o ea ly-s age ec al cance s
in iew o he low likelihood o lympha ic me as asis in T1/T2 umou s
(12–22 %) [21,22].
Appel e al. [23] demons a ed a clea dose– esponse ela ionship in
pa ien s wi h locally ad anced ec al cance who unde wen neo-
adju an chemo adia ion. The he apeu ic e icacy o adia ion elies on
balancing umou con ol and minimising side e ec s in no mal issues.
Despi e ad anced p ecision in ex e nal adio he apy echniques,
achie ing accu a e umou i adia ion wi hou damaging nea by
heal hy issues emains challenging [24]. CXB has he ad an age o
deli e ing a high adia ion dose di ec ly o he umou (20–30 Gy/ses-
sion), wi h a apid dose all-o as issue dep h inc eases due o i s low
ene gy (50kVp), (50 % o he dose a 5 mm dep h and 30 % a 10 mm
dep h), he eby minimising damage o he su ounding no mal issues
[25,26].
Al hough he oncological ou comes ollowing CXB alone may no be
compa able o he s anda d su gical esul s [27], i o e s signi ican
ad an ages o ce ain pa ien s, pa icula ly hose who ha e limi ed
capaci y o unde go su gical p ocedu es. CXB is an ambula o y ea -
men ha gene ally does no equi e gene al anaes hesia, making i
sui able o pa ien s who a e a high su gical isk due o ad anced age o
mul iple como bidi ies. Addi ionally, pa ien s can esume hei daily
ac i i ies soon a e ea men [26,27]. These esul in lowe o e all
ea men cos s o his he apy compa ed o majo su gical p ocedu es
[28]. Fu he mo e, CXB ea men due o i s limi ed pene a ion p op-
e ies, a oids dis up ion o he su gical meso- ec al plane. This is an
impo an ad an age o e local excision, which can impac pos -su gical
mo bidi ies i subsequen sal age comple ion su ge y is equi ed
ollowing local ea men ailu e [29,30].
Al hough nume ous s udies o e he pas se en decades ha e
examined he ou comes o CXB alone, he e has been a lack o ecen
mul i-cen e epo s wi h meaning ul numbe s o pa ien s. We he e o e
Fig. 1. Flowcha o s udy p o ile.
N. Wah Than e al.
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
2
conduc ed his mul i-ins i u ional s udy o e alua e he e icacy o sole
CXB ea men wi h cu a i e in en , pa icula ly in he olde popula ion
who we e conside ed high su gical isk o hose who declined su ge y
o a ious easons. We also assessed he p ognos ic ac o s in luencing
oncological ou comes and he ole abili y o ea men .
Ma e ials and me hods
Pa ien selec ion
This e ospec i e mul i-cen e s udy u ilised da a om he Guild o d
Colo ec al Da abase Sys em, a p ospec i ely main ained na ional da a-
base employed by ou UK CXB ea men cen es: S . Luke’s Cance
Cen e (Guild o d), Cla e b idge Cance Cen e (Li e pool), No ing-
ham Ci y Hospi al, and Queen’s Oncology Cen e (Hull), as well as
Uppsala Cance Uni in Sweden. The s udy included all consecu i e
pa ien s wi h well/mode a ely di e en ia ed, (cT1-2,N0,M0) ec al
adenoca cinoma who ecei ed CXB ea men alone wi h cu a i e in en
be ween 2009 and 2021. Pa ien s wi h mo e ad anced umou s ages
(cT3/T4,N1, o M1) we e excluded, as CXB alone is unlikely o cu e such
cases due o i s limi ed pene a ion in o deepe issues. We also excluded
pa ien s who ecei ed CXB alone as adju an ea men a e local
excision o o luminal eg ow h du ing wa ch-and-wai a e neo-
adju an (chemo) adia ion, as hese cases ha e been analysed sepa-
a ely [12,31]. A e ob aining app o al om all pa icipa ing
ins i u ions, we collec ed da a on pa ien and umou cha ac e is ics/
s aging, ea men de ails, and ollow-up in o ma ion. Fo missing da a
no eco ded in he sys em, we e ie ed in o ma ion whe e possible
om local pa ien eco ds.
Pa ien assessmen and CXB ea men
Baseline umou cha ac e is ics and s aging we e e alua ed h ough
clinical examina ion, endoscopic assessmen , his ological con i ma ion,
c oss-sec ional imaging (magne ic esonance imaging (MRI)), whichwas
mainly used o de e mining umou and nodal s age unless i was
con aindica ed (e.g. pa ien wi h a ca diac pacemake ) and compu ed
omog aphy (CT) (ches and abdomen) o exclude any dis an me as a-
ses. FDG-PET/CT was no ou inely pe o med unless i was needed o
e alua e an equi ocal inding on a con as -enhanced CT o MRI scan o
Table 1
Pa ien and umou cha ac e is ics o he whole and sub-g oups.
Cha ac e is ics To al Based on easons o ha ing sole CXB Based on T-s age
n =76 (%) Fi High isk P e ious RT P alue T1-N0-M0 T2-N0-M0 P alue
n =25(%) n =31(%) n =20(%) n =27(%) n =49(%)
Median ollow-up (IQR) (mon hs) 26(12–49) 43(19–64) 25(12–40) 16(9–41) 0.03 44(14–60) 24(11–42) 0.03
ǂ
Age (yea s) Median (IQR) 78(67–84) 75(65,85) 81(67,86) 77(68–81) 0.21 74(67–82) 80(67–84) 0.54
ǂ
Age g oup 48-<65 yea s 14(18) 7(28) 3(10) 4(20) 4(15) 10(20)
≥65-98 yea s 62(82) 18(72) 28(90) 16(80) 23(85) 39(80)
Gende Male 49(65) 17(68) 19(61) 13(65) 0.87 20(74) 29(59) 0.19*
Female 27(35) 8(32) 12(39) 7(35) 7(26) 20(41)
WHO PS 0–1 45(59) 22(88) 9(29) 14(70) <0.001 21(78) 24(49) 0.04*
02-Ma 27(36) 3(12) 20(65) 4(20) 6(22) 21(43)
No eco ded 4(5) 2(6) 2(10) 0(0) 4(8)
Re used su ge y 34(45) 25(100) 3(10) 6(30) <0.001 13(48) 23(47) 0.66*
Reason ha ing CXB Fi 28(37) 14(52) 14(29) 0.10*
High isk 29(38) 9(33) 20(41)
P io pel ic RT 19(25) 4(15) 15(31)
TNM s age T1N0M0 27(36) 12(48) 11(35) 4(20) 0.15
T2N0M0 49(64) 13(52) 20(65) 16(80)
G ade Well 4(5) 3(12) 1(3) 0(0) 0.2 2(7) 2(4) 0.54*
Mode a e 42(55) 16(64) 16(52) 10(50) 16(59) 26(53)
Unspeci ied 18(24) 3(12) 8(26) 7(35) 4(15) 14(29)
No eco ded 12(16) 3(12) 6(19) 3(15) 5(19) 7(14)
Tumou mo phology Exophy ic 38(50) 11(44) 16(52) 11(55) 0.58 11(41) 27(55) 0.31*
Fla /Ulce a ed 6(8) 1(4) 2(6) 3(15) 0(0) 6(12)
No eco ded 32(42) 13(52) 13(42) 6(30) 16(59) 16(33)
Tumou size Mean (cm) 2.4 ±1.0 2.3 ±1.0 2.2 ±0.9 2.8 ±1.2 0.19 2.3 ±1.3 2.4 ±0.9 0.31
ǂ
Tumou size g oup ≤3cm 54(71) 17(68) 25(81) 12(60) 0.78 18(67) 36(73) 1.0*
>3–4.3 cm 6(8) 2(8) 2(6) 2(10) 2(7) 4(6)
No eco ded 16(21) 6(24) 4(13) 6(30) 7(26) 9(21)
Dis ance om he anal e ge 3-≤6cm 48(63) 14(56) 20(65) 14(70) 0.47 20(74) 28(57) 0.04*
>6–12 cm 20(26) 7(28) 10(32) 3(15) 3(11) 17(35)
No eco ded 8(11) 4(16) 1(3) 3(15) 4(15) 4(7)
CXB o al dose 90 Gy 21(28) 8(32) 10(32) 3(15) 0.34 4(15) 17(35) 0.06*
110–120 Gy 55(72) 17(68) 21(68) 17(85) 23(85) 32(65)
IQR: In e qua ile Range, WHO: Wo ld Heal h O ganiza ion, CXB: Con ac X- ay B achy he apy, ǂ=Mann-Whi ney U es , *=
χ
2
es .
Table 2
Oncological ou comes o he whole and sub-g oups.
Cha ac e is ics To al
n =76 (%)
Based on easons o ha ing sole CXB Based on T-s age
Fi
n =25(%)
High isk
n =31(%)
P e ious RT
n =20(%)
P alue
(
χ
2
es )
T1-N0-M0
n =27(%)
T2-N0-M0
n =49(%)
P alue
(
χ
2
es )
Clinical comple e esponse 62(82) 23(92) 25(81) 14(70) 0.17 25(93) 37(76) 0.05
Residual disease 14(18) 2(8) 6(19) 6(30) 2(7) 12(24)
Local eg ow h 11/62(18) 5/23(22) 2/25(8) 4/14(29) 0.03 4/25(16) 7/37(19) 0.95
Regional elapse 2(3) 1(4) 0(0) 1(5) 0.36 2(7) 0(0) 0.12
Dis an elapse 2(3) 0(0) 1(3) 1(5) 0.38 0(0) 2(4) 0.54
N. Wah Than e al.
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
3
in pa ien s who had s ong con aindica ions o IV con as
adminis a ion.
Be o e s a ing CXB ea men , pa ien s we e e iewed a he local
CXB mul i-disciplina y eam (MDT) mee ing o de e mine he sui abili y
and in en o ea men . Each pa ien was counselled o ully unde s and
ha CXB alone is no a s anda d o ca e o ea ly-s age ec al cance and
ha hey may need o conside su ge y i he e is esidual umou o
local eg ow h a e CXB. All pa ien s p o ided in o med consen be o e
ea men commencemen .
CXB was deli e ed as an ou pa ien ea men using he Papillon-50
©machine (50kVp X- ays (HVL 0.64 Al, 2.7 mA), A iane, Al e on, UK),
20–30 Gy pe ac ion deli e ed e e y 2 weeks apa , h ough a ec al
ea men applica o (size 30, 25, o 22 mm) a a ocal sou ce su ace
dis ance o 29, 32, o 38 mm espec i ely. A s anda d dose o 90 Gy
( ec al mucosal su ace dose) was deli e ed in 3 ac ions o e 4 weeks,
wi h a ou h 20 Gy dose ( o al 110 Gy) being adminis e ed o selec ed
pa ien s who had minimal isible and/ palpable umou s s ill p esen
a e he hi d ac ion.
Follow-up
Pa ien s who achie ed a comple e/nea Clinical Response (cCR/
nCR) a 8–12 weeks ollowing comple ion o ea men unde wen eg-
ula assessmen s, including digi al ec al examina ion, lexible
sigmoidoscopy o ec oscopy a hei local cen e and CXB cen e
al e na i ely, and MRI scans a subsequen 12–14 week in e als du ing
he i s 2 yea s whe e he likelihood o ecu ence is highes . Subse-
quen ly, e alua ions we e conduc ed e e y 6 mon hs in he 3 d yea .
Usually, only endoscopic examina ions we e pe o med in he 4 h and
5 h yea s. Pa ien s who did no achie e cCR/nCR, which was con i med
by iple assessmen (DRE, endoscopy, and MRI) wi h/wi hou his o-
logical con i ma ion, by 24 weeks we e conside ed o su gical ea -
men op ions i hey we e ag eeable and i enough.
Ou come measu es
Oncological ou comes we e e alua ed o he whole g oup and sub-
g oups based on umou s age (T1 e sus T2) and he easons o un-
de going sole CXB wi hou in ol ing EBRT. The pa ien s we e di ided
in o 3 g oups as ollows; hose pa ien s who we e i enough o su ge y
bu e used (g oup A), hose who had a high isk o su ge y due o age
and/o medical como bidi ies (g oup B), and hose who had a his o y o
p io pel ic adio he apy o o he malignancies including p os a e (n =
13), gynaecological (n =6), and bladde (n =1) cance s (g oup C). The
p ima y endpoin s included cCR, local con ol a e (LCR), disease- ee
su i al (DFS), and o e all su i al (OS). Disease- ee su i al o pa-
ien s who ha e achie ed cCR was calcula ed om he da e o he las
adio he apy ea men o he da e o loco egional ecu ence a e R0/
R1 esec ion o he p ima y umou , non-sal ageable local eg ow h/R2
sal age esec ion, he occu ence o a second p ima y, dis an me as-
asis, o las ollow-up. Fo hose who had unde gone sal age su ge y o
hei esidual disease, disease- ee su i al was om he da e o R0/R1
esec ion o he p ima y umou o he da e o loco egional ecu ence,
he occu ence o a second p ima y, dis an me as asis, o las ollow-up.
O e all su i al was de ined as he pe iod om he da e o diagnosis o
he da e o he las da a e iew o dea h om any cause. Seconda y
ou comes in ol ed assessing he in luence o pa ien and umou ac o s
on oncological ou comes and pos -CXB adia ion oxici ies using Com-
mon Te minology C i e ia o Ad e se E en s (CTCAE) c i e ia e sion
5.0 [36].
S a is ical analysis
Quan i a i e da a we e exp essed as medians wi h in e qua ile
anges (IQR) o means wi h s anda d de ia ions (SD), while ca ego ical
da a we e epo ed as coun s wi h pe cen ages. Ca ego ical a iables
we e compa ed using he
χ
2 es , wi h Fishe ’s exac es ( wo- ailed)
employed when necessa y. Con inuous a iables, which we e no no -
mally dis ibu ed, we e compa ed using he independen -samples Mann-
Fig. 2A. Flow diag am illus a ing he oncological ou comes o sub-g oups based on T-s age.
N. Wah Than e al.
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
4
Whi ney U es . Su i al di e ences we e examined wi h Kaplan-Meie
cu es, and he Log- ank es was used o s a is ical assessmen . Asso-
cia ions be ween umou cha ac e is ics and su i al isks we e ana-
lysed using Cox p opo ional haza ds models, while logis ic eg ession
was used o e alua e bina y ma gin ou comes. A p- alue o <0.05 was
conside ed s a is ically signi ican . S a is ical analyses we e conduc ed
using R e sion 4.3.2.
Resul s
F om 2009 o 2021, 140 pa ien s in he da abase we e ea ed solely
wi h CXB. Howe e , only 76 pa ien s we e eligible o he s udy a e
excluding hose who had mo e ad anced s ages (cT3-4/N1/M1) (n =
39), indi iduals no ha ing accu a e s aging (cTx/Nx/Mx) (n =8), pa-
ien s who had been los o ollow-up (n =14) and hose who unde wen
combined ea men wi h high-dose- a e b achy he apy (n =3). Onco-
logical and clinical ou comes we e analysed o he en i e g oup and
sub-g oups based on he umou s age and he easons o adminis e ing
CXB alone. De ailed s udy cha ac e is ics a e p esen ed in Fig. 1.
Whole g oup analysis
Wi h a median ollow-up o 26(IQR: 12–49) mon hs, he median age
o pa ien s was 78(IQR: 67–84) yea s and he majo i y (82 %) we e aged
be ween 65–98 yea s. App oxima ely 47 % o pa ien s, despi e being
appa en ly i , declined su ge y. The mean umou size was 2.4 ±1.0
cm. Demog aphic da a o he whole g oup and subg oups a e shown in
Table 1.
The ini ial cCR a e was 82 % and local eg ow h, de ined as a
eg ow h a he si e o he o iginal umou a which CXB had been
deli e ed, occu ed in 18 % o pa ien s wi hin 7–43 (median: 14) mon hs
a e he las ea men , esul ing in an o e all 3-yea ac ua ial local
con ol a e o 84 %. The one-, h ee- and i e-yea DFS we e 80 %(95 %
CI:73–95), 70 %(95 %CI:60–82), and 66 %(95 %CI:53–82) espec i ely
and OS we e 97 %(95 %CI:94–100), 75 %(95 %CI:70–87), and 58 %(95
%CI:48–72) o e he same pe iods. (Figs. 3A and 4A) Regional elapse
occu ed in only wo pa ien s (who bo h had T1 umou s) (3 %), and
nodal elapse was no obse ed in any pa ien s. Two pa ien s (3 %)
expe ienced dis an elapses (bo h had T2 umou s). The comp ehensi e
ou comes wi h absolu e numbe s o he whole g oup and sub-g oups
a e p esen ed in Table 2 and Figs. 2A and 2B.
Sub-g oup analyses
Based on he T-s age
A o al o 76 pa ien s we e included: consis ing o T1 (n =27) and T2
(n =49) pa ien s. The median ages we e 74(IQR: 67–82) yea s and 80
(IQR: 67–84) yea s. The median ollow-up pe iods we e 44(IQR: 14–60)
mon hs and 24(IQR: 11–42) mon hs espec i ely.
The cCR a es o T1 and T2 pa ien s we e 93 % and 76 % (p =0.05).
Local eg ow h a es we e no signi ican ly di e en be ween g oups
(16 % s 19 %, p =0.95) wi h 3-yea ac ua ial local con ol a es o (90
% s 80 %, p =0.53). Bo h DFS and OS did no show s a is ical di e -
ences be ween T1 and T2 pa ien s wi h DFS a es o 82 % s 78 %, 78 %
s 67 %, and 72 % s 67 % a 1 yea , 3 yea s and 5 yea s espec i ely
[HR:1.2(95 %CI: 0.4, 3.1), p =0.58]. Rega ding OS, hese we e 96 % s
98 %, 85 % s 70 %, and 70 % s 52 % a 1 yea , 3 yea s and 5 yea s
[HR:1.6(95 %CI:0.8, 3.2), p =0.15]. (Figs. 3B and 4B).
Fig. 2B. Flow diag am illus a ing he oncological ou comes o sub-g oups based on easons o ha ing CXB alone. G oup A: hose i o su ge y bu e using su ge y,
G oup B: hose a high isk o su ge y due o ad ancing age/medical como bidi ies, G oup C: hose wi h a his o y o p e ious pel ic adio he apy, cCR: clinical
Comple e Response, APER; Abdomino Pe i oneal Excision o Rec um, LAR: Low An e io Resec ion, TEMS: T ansanal Endoscopic Mucosal Excision, BSC: Bes
Suppo i e Ca e, NA: no a ailable in o ma ion o sal age ea men .
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Based on easons o ha ing CXB alone
O he 76 pa ien s, 25 belonged o G oup A ( i bu e used su ge y),
31 o G oup B (high isk o su ge y), and 20 o G oup C (his o y o p io
pel ic adio he apy). The median ollow-up pe iods we e 43[IQR:
19–64] mon hs, 25[IQR: 12–40] mon hs, and 16[IQR: 9–41] mon hs.
The ini ial cCR a es we e 92 %, 81 %, and 70 % (p =0.17) o g oups
A, B, and C. G oups A (22 %) and C (29 %) exhibi ed signi ican ly highe
local eg ow h a es han g oup B (8 %) (p =0.03). The 3-yea local
con ol a es o g oups A, B, and C we e 80 %, 95 %, and 75 % (p =
0.32). DFS was no signi ican ly di e en ac oss g oups: (86 %, 86 %, 60
%) a 1 yea ; (70 %, 86 %, 48 %) a 3 yea s; and (65 %,78 %, 48 %) a 5
yea s o g oups A, B, and C [HR: 2.21(95 %CI: 0.70, 6.92), p =0.180].
Howe e , he OS was signi ican ly lowe in g oups B [HR:2.54(95 %
CI:1.17, 5.59), p =0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p =0.03]
compa ed o g oup A: (100 %, 100 %, 90 %) a 1 yea ; (97 %, 65 %, 60
%) a 3 yea s, and (75 %, 55 %, 44 %) a 5 yea s o g oup A, B, and C
espec i ely. (Figs. 3C and 4C).
P edic i e ac o s
Pa ien s wi h a his o y o p e ious pel ic adio he apy we e ound o
ha e a lowe likelihood o achie ing cCR. The pa ien ’s age, pe o -
mance s a us, high isk o su ge y, and his o y o p io pel ic adia ion
we e signi ican p edic o s o o e all su i al (Supplemen a y
Table S1).
Follow-up and sal age ea men s
Among he 14 pa ien s who had esidual disease ollowing CXB, 5
op ed o sal age su ge ies: abdominope ineal esec ions (APER) =3,
Fig. 3A. Kaplan-Meie cu e o disease- ee su i al o he whole g oup. Fig. 3B. Kaplan-Meie cu e o disease- ee su i al based on T-s age.
N. Wah Than e al.
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low an e io esec ion (LAR) =1, and ansanal endoscopic mic osu -
ge y (TEMS) =1, wi h all achie ing R0 esec ions excep R1 esec ion in
he TEMS case. Two pa ien s declined su ge y and ins ead ecei ed he
bes suppo i e ca e, while he emaining 7 we e conside ed high su -
gical isk; o hese, 2 unde wen ex e nal beam adio he apy (EBRT), 1
ecei ed pallia i e chemo he apy, and 4 we e gi en he bes suppo i e
ca e.
O he 11 pa ien s who expe ienced local umou eg ow h, 4 un-
de wen APER (all R0 esec ions), and 1 pa ien , al hough i enough,
e used u he ea men . The emaining 6 pa ien s we e un i o su -
ge y: 2 ecei ed pallia i e adio he apy (EBRT and u he CXB) and 4
ecei ed he bes suppo i e ca e. Among he wo pa ien s who expe i-
enced pel ic elapse, one unde wen sal age su ge y, while he o he ,
who was un i o su ge y, ecei ed he bes suppo i e ca e.
Pos - adia ion oxici ies
Toxici y p o iles we e a ailable o 47 ou o he 76 pa ien s. The
p edominan pos - ea men symp om was la e G1-2 ec al bleeding;
obse ed in 12 pa ien s (26 %). G ade 3 bleeding, necessi a ing a gon
beam ea men , occu ed in only wo pa ien s (4.2 %). E a ic bowel,
ec al pain, and u gency sugges i e o acu e p oc i is symp oms (G1-2)
mani es ed in 4 pa ien s (9 %). None o he pa ien s epo ed symp oms
sugges i e o impai ed anal sphinc e unc ion.
Discussion
In his s udy, he o e all cCR a e was 82 % ( ange: 70–93) while
p e ious s udies ha e alua ed he e icacy o CXB alone ea men
be ween 1951 and 2006 [13,14,32–42], epo ed a cu e a e o 63–95 %
Fig. 3C. Kaplan-Meie cu e o disease- ee su i al based on easons o
ha ing CXB alone.
Fig. 4A. Kaplan-Meie cu e o o e all su i al o he whole g oup.
N. Wah Than e al.
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
7
(wi h 5–20 % a e o esidual disease). The local eg ow h a e in ou
s udy was also compa able o hose epo ed in p e ious CXB alone
s udies (18(8–29)% s 5–28 %). The dis an elapse a e was much lowe
in ou s udy han p e ious indings (3 % s 6–13 %), and no pa ien s
expe ienced nodal elapse, whe eas one p e ious s udy epo ed a 7 %
nodal elapse a e [13]. The 5-yea DFS a e was 66(48–78)% s 66–97
% in he his o ic se ies, and he OS a e was 58(44–75)% s 48–84 %.
(Supplemen a y Table S2) The indings om ou s udy a e he e o e
gene ally consis en wi h he esul s published in hese his o ic se ies.
Howe e , ea lie s udies u ilised a ious s aging sys ems and me hods
o assessing esponse, p ima ily using DRE and TRUS/ERUS. The
de elopmen o mode n imaging echnologies o mo e accu a e s aging
since hose s udies we e conduc ed, could po en ially in oduce bias
when di ec ly compa ing his o ical esul s wi h hose ound in ou s udy.
Hab -Gama e al demons a ed cCR a es anging om 57-86 %,
loco egional ecu ence a es be ween 20–31 %, and dis an elapse
a es o 11–26 % in a coho o 81 pa ien s wi h ea ly ec al cance s
(cT2N0M0) who we e ea ed wi h s anda d (50.4 Gy) and ex ended
chemo adia ion (54 Gy) [15]. The isk o local ecu ence a e local
excision alone, wi hou adju an adio he apy, o T1 umou s was
4–13 % and 19–29 % o T2 umou s [43,44]. The he e ogeneous na u e
o pa ien cha ac e is ics in ou coho limi s di ec compa isons o DFS
and OS be ween ou s udy and hese o he o gan-p ese ing s udies.
Despi e hese cons ain s, he local con ol a e epo ed in ou coho
was compa able o hose obse ed wi h hese o gan-p ese ing op ions,
while achie ing a lowe incidence o dis an elapse.
Pa ien s who had T2 umou s, a his o y o p e ious pel ic adio-
he apy, and who we e a high isk o su ge y, exhibi ed lowe a es o
cCR. Howe e , no s a is ical signi icance was obse ed, which may be
Fig. 4B. Kaplan-Meie cu e o o e all su i al based on T-s age. Fig. 4C. Kaplan-Meie cu e o o e all su i al based on easons o ha ing
CXB alone.
N. Wah Than e al.
Clinical and T ansla ional Radia ion Oncology 49 (2024) 100851
8
a ibu ed o he ela i ely small coho sizes. In con as , pa ien s who
we e high- isk- o -su ge y showed a signi ican ly lowe isk o local
eg ow h han he o he g oups, he eby achie ing a highe a e o DFS.
Those pa ien s who had p e ious adia ion exposu e o hei p e ious
un ela ed ype o umou also expe ienced an inc eased isk o local
umou elapse, and lowe DFS and OS. This may be ela ed o he
p esence o adio esis an umou clones and a g ea e p opo ion o T2
umou s wi hin his g oup. O e all, we ound no signi ican di e ences
in ou comes be ween pa ien s wi h T1 and T2 umou s, simila o ob-
se a ions in p e ious s udies. Howe e , he esul s o ou s a is ical
analysis may ha e been in luenced by he small sample size o ou
coho .
P e ious adia ion exposu e was iden i ied as an ad e se p edic o
o local umou con ol and OS, which could be a ibu ed o he po-
en ial de elopmen o adio esis an umou clones [45]. Mo eo e , in
his g oup, CXB alone was used in sligh ly highe - isk se ings (such as
T2 umou s) whe e a combina ion o EBRT and CXB would p obably
ha e been ecommended i p e ious adia ion had no been adminis-
e ed o his a ea.
No se ious ad e se e ec s we e epo ed in his s udy, wi h compa-
able a es o sel -limi ing adia ion oxici ies, simila o o he s udies
[35,46]. No pa ien s epo ed symp oms indica i e o impai ed anal
sphinc e unc ion, a common pos - ea men side e ec o TAE and
(chemo) adia ion [17,47].
This s udy has se e al limi a ions. The da a p ima ily elied on a
da abase ha was designed o egis e de ails such as p ima y ea men ,
oxici ies, and su gical in o ma ion. Un o una ely, some in o ma ion,
pa icula ly long- e m ou comes o pa ien s who unde wen sal age
he apies ollowing CXB ailu es a ce ain cen es, was no eco ded.
These pa ien s we e e u ned o he ca e o colo ec al su geons who did
no pa icipa e in he p ojec , limi ing ou abili y o ho oughly assess
he easibili y o sal age ea men and he long- e m ou comes o hese
pa ien s. Mo eo e , he ela i ely small coho size and une en dis i-
bu ion o pa ien s be ween sub-g oups migh ha e impac ed he s a is-
ical compa ison o ou comes. Addi ionally, he conside able
he e ogenei y among pa ien ac o s wi hin ou coho may ha e
in oduced po en ial bias when assessing he esul s o sole CXB and
compa ing hese wi h ou comes om o he ea men op ions. The e-
o e, we ecommend conduc ing p ospec i e s udies ha adequa ely
con ol o pa ien and umou con ounding ac o s o p o ide a mo e
obus unde s anding o he ole o sole CXB ea men compa ed o
a ious o he o gan-p ese ing ea men op ions.
Conclusions
Ou s udy con i med a high a e o cCR, sa is ac o y local umou
con ol, and disease- ee su i al in a mode n coho o ea ly ec al
cance pa ien s (cT1/cT2, cN0, cM0) who ecei ed CXB alone. The lowe
o e all su i al a e likely e lec s he cha ac e is ics o he elde ly and
como bid coho in ou s udy popula ion. In e io oncological ou comes
we e also obse ed in pa ien s wi h a his o y o p io pel ic adio-
he apy. Ne e heless, conside ing i s se e al ad an ages o e o he
o gan-p ese ing ea men op ions, CXB alone can be conside ed a
iable al e na i e o selec ed pa ien s.
CRediT au ho ship con ibu ion s a emen
Ngu Wah Than: Concep ualiza ion, Me hodology, So wa e, Fo mal
analysis, In es iga ion, Da a cu a ion, W i ing – o iginal d a , Visuali-
za ion. D. Ma k P i cha d: Concep ualiza ion, Me hodology, W i ing –
e iew & edi ing, Da a cu a ion, Supe ision, P ojec adminis a ion.
Da id M. Hughes: Me hodology, So wa e, W i ing – e iew & edi ing,
Da a cu a ion. Kai Shing Yu: Resou ces, Da a cu a ion. Helen S. Min-
naa : Resou ces, Da a cu a ion. Amandeep Dhadda: Resou ces, Da a
cu a ion, W i ing – e iew & edi ing. Jamie Mills: Resou ces. Joakim
Folkesson: Resou ces, Da a cu a ion, W i ing – e iew & edi ing. Calin
Radu: Resou ces, Da a cu a ion, W i ing – e iew & edi ing. C.A.
Duckwo h: Supe ision. Helen Wong: Resou ces, Da a cu a ion.
Muneeb Ul Haq: Da a cu a ion. Raja am S ipadam: Resou ces, Da a
cu a ion. Ma k D. Halling-B own: Resou ces, Da a cu a ion. Alexan-
d a J. S ewa : Resou ces, Da a cu a ion, W i ing – e iew & edi ing.
A hu Sun Myin : Concep ualiza ion, Resou ces, Da a cu a ion,
W i ing – e iew & edi ing, Supe ision.
Decla a ion o compe ing in e es
The au ho s decla e ha hey ha e no known compe ing inancial
in e es s o pe sonal ela ionships ha could ha e appea ed o in luence
he wo k epo ed in his pape .
Acknowledgemen s
The wo k o he i s au ho was unded by he Eu opean Union’s
Ho izon 2020 esea ch and inno a ion p og amme, Ma ie Skłodowska-
Cu ie g an ag eemen numbe 857894—CAST. The colo ec al da abase
is unded by he cha i ies BRIGHT (cha i y numbe : 1064857) and GUTS
(cha i y numbe : 1026791)
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h ps://doi.
o g/10.1016/j.c o.2024.100851.
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